85 results on '"Jong J. Kim"'
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2. The link between abnormal calcium handling and electrical instability in acquired long QT syndrome – Does calcium precipitate arrhythmic storms?
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Jong J. Kim, Guy Salama, and Jan Němec
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0301 basic medicine ,medicine.medical_specialty ,Long QT syndrome ,Intracellular Space ,Biophysics ,chemistry.chemical_element ,030204 cardiovascular system & hematology ,Calcium ,Catecholaminergic polymorphic ventricular tachycardia ,Article ,Afterdepolarization ,Troponin C ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Optical mapping ,medicine ,Animals ,Humans ,Myocyte ,Repolarization ,cardiovascular diseases ,Molecular Biology ,Sex Characteristics ,medicine.disease ,Electrophysiological Phenomena ,Long QT Syndrome ,030104 developmental biology ,Endocrinology ,chemistry ,cardiovascular system ,Cardiology - Abstract
Release of Ca(2+) ions from sarcoplasmic reticulum (SR) into myocyte cytoplasm and their binding to troponin C is the final signal form myocardial contraction. Synchronous contraction of ventricular myocytes is necessary for efficient cardiac pumping function. This requires both shuttling of Ca(2+) between SR and cytoplasm in individual myocytes, and organ-level synchronization of this process by means of electrical coupling among ventricular myocytes. Abnormal Ca(2+) release from SR causes arrhythmias in the setting of CPVT (catecholaminergic polymorphic ventricular tachycardia) and digoxin toxicity. Recent optical mapping data indicate that abnormal Ca(2+) handling causes arrhythmias in models of both repolarization impairment and profound bradycardia. The mechanisms involve dynamic spatial heterogeneity of myocardial Ca(2+) handling preceding arrhythmia onset, cell-synchronous systolic secondary Ca(2+) elevation (SSCE), as well as more complex abnormalities of intracellular Ca(2+) handling detected by subcellular optical mapping in Langendorff-perfused hearts. The regional heterogeneities in Ca(2+) handling cause action potential (AP) heterogeneities through sodium-calcium exchange (NCX) activation and eventually overwhelm electrical coupling of the tissue. Divergent Ca(2+) dynamics among different myocardial regions leads to temporal instability of AP duration and - on the patient level - in T wave lability. Although T-wave alternans has been linked to cardiac arrhythmias, non-alternans lability is observed in pre-clinical models of the long QT syndrome (LQTS) and CPVT, and in LQTS patients. Analysis of T wave lability may provide a real-time window on the abnormal Ca(2+) dynamics causing specific arrhythmias such as Torsade de Pointes (TdP).
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- 2016
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3. Synchronous Systolic Subcellular Ca 2+ -Elevations Underlie Ventricular Arrhythmia in Drug-Induced Long QT Type 2
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Jong J. Kim, Guy Salama, Qiao Li, and Jan Němec
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medicine.medical_specialty ,Time Factors ,Thiazepines ,Long QT syndrome ,Diastole ,Action Potentials ,Dofetilide ,In Vitro Techniques ,Article ,Afterdepolarization ,Heart Rate ,Physiology (medical) ,Internal medicine ,Phenethylamines ,medicine ,Animals ,Myocyte ,Repolarization ,Myocytes, Cardiac ,Calcium Signaling ,Systole ,Sulfonamides ,Ryanodine receptor ,business.industry ,medicine.disease ,Voltage-Sensitive Dye Imaging ,Perfusion ,Disease Models, Animal ,Long QT Syndrome ,Sarcoplasmic Reticulum ,Cardiology ,Female ,Rabbits ,Cardiology and Cardiovascular Medicine ,business ,Anti-Arrhythmia Agents ,medicine.drug - Abstract
Background— Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca 2+ -release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long-QT syndrome. A crucial missing link is how such a stochastic process can overcome the source–sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias. Methods and Results— Optical maps of action potentials and Ca 2+ -transients from Langendorff rabbit hearts were measured at low (150×150 μm 2 /pixel) and high (1.5×1.5 μm 2 /pixel) resolution before and during arrhythmias. Drug-induced long QT type 2, elicited with dofetilide inhibition of IKr (the rapid component of rectifying K+ current), produced spontaneous Ca 2+ -elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca 2+- waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Ca 2+- elevations were synchronous within individual myocytes, appeared 188±30 ms after the action potential-upstroke, occurred during high cytosolic Ca 2+ (40%–60% of peak-Ca 2+ -transients), appeared first in small islands (0.5×0.5 mm 2 ) that enlarged and spread throughout the epicardium. Synchronous systolic Ca 2+- elevations preceded voltage-depolarizations (9.2±5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca 2+ -transient-durations and action potential-durations. Early afterdepolarizations originating from sites with the steepest gradients of membrane-potential propagated and initiated arrhythmias. Interestingly, more complex subcellular Ca 2+ -dynamics (multiple chaotic Ca 2+ -waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca 2+ -elevations and arrhythmias. Conclusions— The results indicate that systolic and diastolic Ca 2+ -elevations emanate from sarcoplasmic reticulum Ca 2+ -release and systolic Ca 2+ -elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca 2+ , which overcomes source–sink mismatch to trigger arrhythmias in intact hearts.
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- 2015
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4. Mechanism of automaticity in cardiomyocytes derived from human induced pluripotent stem cells
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Lei Yang, Aaron D. Kaplan, Bin Sun, Randall L. Rasmusson, Jong J. Kim, Guy Salama, Glenna C.L. Bett, Xiaodong Zhu, Barry London, and Bo Lin
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Patch-Clamp Techniques ,Cellular differentiation ,Genetic Vectors ,Induced Pluripotent Stem Cells ,Action Potentials ,Biology ,Transfection ,Microtubules ,Ryanodine receptor 2 ,Sodium-Calcium Exchanger ,Article ,Cell Line ,Pacemaker potential ,Tetracaine ,Caffeine ,Animals ,Humans ,Ivabradine ,Myocytes, Cardiac ,Patch clamp ,Induced pluripotent stem cell ,Molecular Biology ,health care economics and organizations ,Aniline Compounds ,Sodium-calcium exchanger ,Phenyl Ethers ,Isoproterenol ,Cardiovascular Agents ,Cell Differentiation ,Anatomy ,Benzazepines ,Dependovirus ,Cellular Reprogramming ,Embryonic stem cell ,Cell biology ,Sarcoplasmic Reticulum ,Connexin 43 ,Cardiovascular agent ,Calcium ,Cardiology and Cardiovascular Medicine - Abstract
The creation of cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs) has spawned broad excitement borne out of the prospects to diagnose and treat cardiovascular diseases based on personalized medicine. A common feature of hiPS-CMs is their spontaneous contractions but the mechanism(s) remain uncertain.Intrinsic activity was investigated by the voltage-clamp technique, optical mapping of action potentials (APs) and intracellular Ca(2+) (Cai) transients (CaiT) at subcellular-resolution and pharmacological interventions.The frequency of spontaneous CaiT (sCaiT) in monolayers of hiPS-CMs was not altered by ivabradine, an inhibitor of the pacemaker current, If despite high levels of HCN transcripts (1-4). HiPS-CMs had negligible If and IK1 (inwardly-rectifying K(+)-current) and a minimum diastolic potential of -59.1±3.3mV (n=18). APs upstrokes were preceded by a depolarizing-foot coincident with a rise of Cai. Subcellular Cai wavelets varied in amplitude, propagated and died-off; larger Cai-waves triggered cellular sCaTs and APs. SCaiTs increased in frequency with [Ca(2+)]out (0.05-to-1.8mM), isoproterenol (1μM) or caffeine (100μM) (n≥5, p0.05). HiPS-CMs became quiescent with ryanodine receptor stabilizers (K201=2μM); tetracaine; Na-Ca exchange (NCX) inhibition (SEA0400=2μM); higher [K(+)]out (5→8mM), and thiol-reducing agents but could still be electrically stimulated to elicit CaiTs. Cell-cell coupling of hiPS-CM in monolayers was evident from connexin-43 expression and CaiT propagation. SCaiTs from an ensemble of dispersed hiPS-CMs were out-of-phase but became synchronous through the outgrowth of inter-connecting microtubules.Automaticity in hiPS-CMs originates from a Ca(2+)-clock mechanism involving Ca(2+) cycling across the sarcoplasmic reticulum linked to NCX to trigger APs.
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- 2015
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5. Novel and enhanced anti-melanoma DNA vaccine targeting the tyrosinase protein inhibits myeloid-derived suppressor cells and tumor growth in a syngeneic prophylactic and therapeutic murine model
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Kimberly A. Kraynyak, Emma L. Reuschel, Devin J.F. Myles, Niranjan Y. Sardesai, Jian Yan, A Muthumani, Daniel K. Choo, Terri H. Finkel, Jong J. Kim, Randolph B. Lyde, DB Weiner, L P Weiner, T C Gorham, Kenneth E. Ugen, Karuppiah Muthumani, and Colleen Tingey
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Cancer Research ,Melanoma, Experimental ,T-Cell Antigen Receptor Specificity ,CD8-Positive T-Lymphocytes ,Biology ,Cancer Vaccines ,DNA vaccination ,Immunomodulation ,Mice ,Immune system ,Immunity ,Tumor Microenvironment ,Vaccines, DNA ,medicine ,Animals ,Humans ,Myeloid Cells ,Melanoma ,Molecular Biology ,Immunity, Cellular ,Tumor microenvironment ,Monophenol Monooxygenase ,Cancer ,medicine.disease ,Immunity, Humoral ,Tumor Burden ,Disease Models, Animal ,Tumor progression ,Immunology ,Myeloid-derived Suppressor Cell ,Cytokines ,Molecular Medicine ,Female ,Immunization - Abstract
Melanoma is the most deadly type of skin cancer, constituting annually ∼ 75% of all cutaneous cancer-related deaths due to metastatic spread. Currently, because of metastatic spread, there are no effective treatment options for late-stage metastatic melanoma patients. Studies over the past two decades have provided insight into several complex molecular mechanisms as to how these malignancies evade immunological control, indicating the importance of immune escape or suppression for tumor survival. Thus, it is essential to develop innovative cancer strategies and address immune obstacles with the goal of generating more effective immunotherapies. One important area of study is to further elucidate the role and significance of myeloid-derived suppressor cells (MDSCs) in the maintenance of the tumor microenvironment. These cells possess a remarkable ability to suppress immune responses and, as such, facilitate tumor growth. Thus, MDSCs represent an important new target for preventing tumor progression and escape from immune control. In this study, we investigated the role of MDSCs in immune suppression of T cells in an antigen-specific B16 melanoma murine system utilizing a novel synthetic tyrosinase (Tyr) DNA vaccine therapy in both prophylactic and therapeutic models. This Tyr vaccine induced a robust and broad immune response, including directing CD8 T-cell infiltration into tumor sites. The vaccine also reduced the number of MDSCs in the tumor microenvironment through the downregulation of monocyte chemoattractant protein 1, interleukin-10, CXCL5 and arginase II, factors important for MDSC expansion. This novel synthetic DNA vaccine significantly reduced the melanoma tumor burden and increased survival in vivo, due likely, in part, to the facilitation of a change in the tumor microenvironment through MDSC suppression.
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- 2014
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6. Calcium oscillations and T-wave lability precede ventricular arrhythmias in acquired long QT type 2
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Jan Němec, Jong J. Kim, Beth Gabris, and Guy Salama
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medicine.medical_specialty ,Long QT syndrome ,Action Potentials ,Dofetilide ,Torsades de pointes ,Paced Rhythm ,Article ,Afterdepolarization ,Electrocardiography ,Nifedipine ,Heart Conduction System ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Repolarization ,business.industry ,Ryanodine receptor ,medicine.disease ,Long QT Syndrome ,Sarcoplasmic Reticulum ,Endocrinology ,Cardiology ,Calcium ,Female ,Rabbits ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Background Alternans of intracellular Ca 2+ (Ca i ) underlies T-wave alternans, a predictor of cardiac arrhythmias. A related phenomenon, T-wave lability (TWL), precedes torsades de pointes (TdP) in patients and animal models with impaired repolarization. However, the role of Ca i in TWL remains unexplored. Objective This study investigated the role of Ca i dynamics on TWL in a noncryoablated rabbit model of long QT syndrome type 2 (LQT2) using simultaneous measurements of Ca i transient (CaT), action potentials (APs), and electrocardiogram (ECG) during paced rhythms and focused on events that precede ventricular ectopy. Methods APs and CaTs were mapped optically from paced Langendorff female rabbit hearts (n = 8) at 1.2-s cycle length, after atrioventricular node ablation. Hearts were perfused with normal Tyrode solution, then with dofetilide (0.5 μM), and reduced [K + ] (2 mM) and [Mg 2+ ] (0.5 mM) to elicit LQT2. Lability of ECG, voltage, and Ca i signals were evaluated during regular paced rhythm, before and after dofetilide perfusion. Results In LQT2, lability of Ca i , voltage, and ECG signals increased during paced rhythm, before the appearance of early afterdepolarizations (EADs). LQT2 resulted in AP prolongation and multiple (1 to 3) additional Ca i upstrokes, whereas APs remained monophasic. When EADs appeared, Ca i rose before voltage upstrokes at the origins of propagating EADs. Interventions (i.e., ryanodine and thapsigargin, n=3 or low [Ca] o and nifedipine, n=4) that suppressed Ca i oscillations also abolished EADs. Conclusion In LQT2, Ca i oscillations (Ca i O) precede EADs by minutes, indicating that they result from spontaneous sarcoplasmic reticulum Ca 2+ release rather than spontaneous I Ca,L reactivation. Ca i O likely produce oscillations of Na/Ca exchange current, I NCX . Depolarizing I NCX during the AP plateau contributes to the generation of EADs by reactivating Ca 2+ channels that have recovered from inactivation. TWL reflects CaTs and APs lability that occur before EADs and TdP.
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- 2010
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7. The magnetic field dependence of the deformation potential materials in the square well confinement potential
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Su H. Lee, Joung Young Sug, and Jong J. Kim
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Quantum phase transition ,Physics ,Condensed matter physics ,Phonon ,response formula and the scattering factor formula ,QC1-999 ,quantum transport theory ,General Physics and Astronomy ,Transition of state ,Electron ,Projection (linear algebra) ,Square (algebra) ,Magnetic field ,equilibrium average projection scheme (eaps) ,electron phonon coupling system ,05.60gg ,the quantum transition line shapes (qtls) ,projected liouville equation method ,the quantum transition line widths (qtlw) ,72.10.di ,Quantum - Abstract
We study the optical Quantum Transition Line Shapes (QTLS) which show the absorption power and the Quantum Transition Line Widths (QTLW) of electron-deformation potential phonon interacting systems. In order to analyze the quantum transition, we compare the magnetic field dependencies of the QTLWand the QTLS on two transition processes, namely the intra-Landau level transition process and the inter-Landau level transition process. We apply the Quantum Transport theory (QTR) to the system in the confinement of electrons by square well confinement potential. We use the projected Liouville equation method with Equilibrium Average Projection Scheme (EAPS).
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- 2008
8. STIM1–Ca 2+ signaling modulates automaticity of the mouse sinoatrial node
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Geoffrey S. Pitt, Jong J. Kim, Jonathan A. Stiber, W. J. Lederer, Nenad Bursac, Igor Nepliouev, Tianyu Li, Elizabeth A. Finch, Paul B. Rosenberg, Albert Y. Sun, Hengtao Zhang, Guiling Zhao, and Victoria Graham
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inorganic chemicals ,medicine.medical_specialty ,Calcium Channels, L-Type ,ORAI1 Protein ,Biology ,Mice ,Internal medicine ,medicine ,Animals ,Myocytes, Cardiac ,Calcium Signaling ,Stromal Interaction Molecule 1 ,Sinoatrial Node ,Calcium signaling ,Mice, Knockout ,Multidisciplinary ,Voltage-dependent calcium channel ,ORAI1 ,Sinoatrial node ,Endoplasmic reticulum ,Cardiac action potential ,STIM1 ,Cell biology ,Sarcoplasmic Reticulum ,Endocrinology ,medicine.anatomical_structure ,PNAS Plus ,Cholinergic ,Calcium ,Calcium Channels - Abstract
Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca(2+) release from internal Ca(2+) stores (Ca(2+) clock) to adjust heart rate to meet hemodynamic demand. Here, we report that stromal interaction molecule 1 (STIM1) and Orai1 channels, key components of store-operated Ca(2+) entry, are selectively expressed in SANCs. Cardiac-specific deletion of STIM1 in mice resulted in depletion of sarcoplasmic reticulum (SR) Ca(2+) stores of SANCs and led to SAN dysfunction, as was evident by a reduction in heart rate, sinus arrest, and an exaggerated autonomic response to cholinergic signaling. Moreover, STIM1 influenced SAN function by regulating ionic fluxes in SANCs, including activation of a store-operated Ca(2+) current, a reduction in L-type Ca(2+) current, and enhancing the activities of Na(+)/Ca(2+) exchanger. In conclusion, these studies reveal that STIM1 is a multifunctional regulator of Ca(2+) dynamics in SANCs that links SR Ca(2+) store content with electrical events occurring in the plasma membrane, thereby contributing to automaticity of the SAN.
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- 2015
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9. Inclusion of Vpr accessory gene in a plasmid vaccine cocktail markedly reduces Nef vaccine effectiveness in vivo resulting in CD4 cell loss and increased viral loads in rhesus macaques
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David B. Weiner, Velpandi Ayyavoo, Dan Conway, Donghui Zhang, Daniel S. Hwang, Jean D. Boyer, Jong J. Kim, Kelledy Manson, Mark L. Bagarazzi, and Karuppiah Muthumani
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General Veterinary ,viruses ,Immunogenicity ,virus diseases ,Biology ,Virology ,Vaccination ,CTL ,Plasmid ,Antigen ,Immunity ,Cytotoxic T cell ,Animal Science and Zoology ,Viral load - Abstract
We compared the immunogenicity of plasmid vaccines containing multiple human immunodeficiency virus (HIV) antigens and found that covaccination with plasmids expressing HIV-1 14 kDa vpr gene product profoundly reduces antigen-specific CD8-mediated cytotoxic T-cell activity (CTL). Interestingly, Th1 type responses against codelivered antigens (pGag-Pol, pNef, etc.) encoded by the plasmid vaccines were suppressed. This suggested that vpr might compromise CD8 T-cell immunity in vivo during infection. A pilot primate vaccine study was designed to test the hypothesis to compare the following groups: unvaccinated controls, animals vaccinated without simean immunodeficiency virus (SIV)-Nef antigen plasmid, and animals covaccinated with the identical plasmid antigen and a plasmid construct encoding SIV Vpr/Vpx. Animals were subsequently challenged intrarectally with pathogenic SIVmac251 after the final vaccination of a multiple immunization protocol. Control animals were all infected and exhibited high viral loads and rapid CD4 + T-cell loss. In contrast, the Nef plasmid-vaccinated animals were also infected but exhibited preservation of CD4 + T-cells and a multilog reduction in viral load compared with controls. Animals covaccinated multiple times with the Nef vaccine and pVpr/Vpx plasmid suffered rapid and profound loss of CD4 + T-cells. These results have important implications for the design of multicomponent and particle vaccines for HIV-1 as well as for our understanding of HIV/SIV pathogenesis in vivo.
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- 2002
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10. HIV-1 viral protein R compromises cellular immune function in vivo
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David B. Weiner, Velpandi Ayyavoo, P. Ramanathan, Donghui Zhang, Karuppiah Muthumani, Jeong-Im Sin, Sagar B. Kudchodkar, Jong J. Kim, Luis J. Montaner, and Nathanael S. Dayes
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viruses ,medicine.medical_treatment ,T cell ,Immunology ,Inflammation ,HIV Antibodies ,Biology ,Interferon-gamma ,Mice ,Immune system ,Antigen ,In vivo ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,Antigen-presenting cell ,Cells, Cultured ,AIDS Vaccines ,Mice, Inbred BALB C ,Gene Products, vpr ,virus diseases ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Cell biology ,Cytokine ,medicine.anatomical_structure ,DNA, Viral ,Female ,Immunization ,medicine.symptom ,T-Lymphocytes, Cytotoxic - Abstract
HIV-1 viral protein R (Vpr) is a virion-associated gene product that profoundly affects T cell proliferation, induces apoptosis and can affect cytokine production in part through interfering with NF-kappa B-mediated transcription from host cells. Collectively, these effects support that Vpr could influence immune activation in vivo. However, this effect of Vpr has not been explored previously. Here we examined the effect of Vpr expression in an in vivo model system on the induction of antigen-specific immune responses using a DNA vaccine model. Vpr co-vaccination significantly altered the immune response to co-delivered antigen. Specifically, in the presence of Vpr, inflammation was markedly reduced compared to antigen alone. Vpr reduced antigen-specific CD8-mediated cytotoxic T lymphocyte activity and suppressed T(h)1 immune responses in vivo as evidenced by lower levels of IFN-gamma. In the presence of Vpr, there is a profound shift in isotype towards a T(h)2 response as determined by the IgG2a:IgG1 ratio. The data support that Vpr compromises antigen-specific immune responses and ultimately effector cell function, thus confirming a strong selective advantage to the virus at the expense of the host.
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- 2002
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11. Coimmunization with IFN- gamma or IL-2, but Not IL-13 or IL-4 cDNA Can Enhance Th1-Type DNA Vaccine-Induced
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Jong J. Kim, Luis J. Montaner, Daniel J. Lee, David B. Weiner, Joo Sung Yang, and Ara A. Chalian
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Immunogen ,medicine.medical_treatment ,Immunology ,Cell Biology ,Biology ,DNA vaccination ,Cytokine ,Immune system ,Virology ,Complementary DNA ,Interleukin 13 ,medicine ,Gene ,Interleukin 4 - Abstract
As we explore the potential improvements to the current DNA vaccine strategies, it may be desirable to investigate methods to improve the level of resulting immune responses. One strategy is the use of cytokine cDNA as molecular adjuvants for DNA-based vaccines. Codelivery of these molecular adjuvants consisting of expression plasmid encoding for cytokines with DNA vaccine constructs is an effective method to modulate the magnitude and direction (humoral or cellular) of the immune responses. We have previously reported on the immunomodulatory effects of codelivering cDNA for interleukin-2 (IL-2) and IL-4 as molecular adjuvants for DNA-based vaccines. In this report, we extend these finding and compare the immunomodulatory effects of IL-2 and IL-4 with those of cDNA for prototypical Thl-type cytokine interferon-y (IFN-gamma) and Th2-type cytokine IL-13. We observed that distinct antigen-specific immune modulation can be achieved by the coinjection of IFN-gamma or IL-13 genes with DNA immunogen cassettes. We observed that IFN-gamma is a strong driver of Thl immune responses. Furthermore, in contrast to previous reports on their similarities in biologic activities, IL-13 and IL-4 cDNA coimmunizations modulated vaccine-induced immune responses differently in this model. Overall, these results further support the potential utility of this strategy as an important tool for the development of vaccines and immune therapies.
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- 2000
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12. Antigen-specific humoral and cellular immune responses can be modulated in rhesus macaques through the use of IFN-γ, IL-12, or IL-18 gene adjuvants
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Michael S. Wyand, Daniel J. Lee, Jong J. Kim, David B. Weiner, Jim Oh, Tzvete Dentchev, Kelledy H. Manson, Liesl K. Nottingham, Michael G. Agadjanyan, Anthony Tsai, Henry C. Maguire, and Kenneth E. Ugen
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medicine.medical_treatment ,HIV Infections ,Biology ,DNA vaccination ,Antigen-Antibody Reactions ,Mice ,Immune system ,Adjuvants, Immunologic ,Vaccines, DNA ,medicine ,Animals ,AIDS Vaccines ,Immunity, Cellular ,Mice, Inbred BALB C ,General Veterinary ,Interleukin-18 ,Interleukin ,T-Lymphocytes, Helper-Inducer ,Interleukin-12 ,Macaca mulatta ,Virology ,Disease Models, Animal ,Cytokine ,Immunization ,Antibody Formation ,Immunology ,Interleukin 12 ,Female ,Simian Immunodeficiency Virus ,Animal Science and Zoology ,Interleukin 18 ,Adjuvant - Abstract
DNA or nucleic acid immunization has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. Moreover, immune responses induced by DNA immunization can be enhanced and modulated by the use of molecular adjuvants. To engineer the immune response in vivo towards more T-helper (Th)1-type cellular responses, we investigated the co-delivery of inteferon (IFN)-gamma, interleukin (IL)-12, and IL-18 genes along with DNA vaccine constructs. We observed that both antigen-specific humoral and cellular immune responses can be modulated through the use of cytokine adjuvants in mice. Most of this work has been performed in rodent models. There has been little confirmation of this technology in primates. We also evaluated the immunomodulatory effects of this approach in rhesus macaques, since non-human primates represent the most relevant animal models for human immunodeficiency virus (HIV) vaccine studies. As in the murine studies, we also observed that each Th1 cytokine adjuvant distinctively regulated the level of immune responses generated. Co-immunization of IFN-gamma and IL-18 in macaques enhanced the level of antigen-specific antibody responses. Similarly, co-delivery of IL-12 and IL-18 also enhanced the level of antigen-specific Th proliferative responses. These results extend this adjuvant strategy in a more relevant primate model and support the potential utility of these molecular adjuvants in DNA vaccine regimens.
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- 1999
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13. CD86 (B7-2) Can Function to Drive MHC-Restricted Antigen-Specific CTL Responses In Vivo
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Michael G. Agadjanyan, Jong J. Kim, Neil Trivedi, Darren M. Wilson, Behjatolah Monzavi-Karbassi, Lake D. Morrison, Liesl K. Nottingham, Tzvete Dentchev, Anthony Tsai, Kesen Dang, Ara A. Chalian, Michael A. Maldonado, William V. Williams, and David B. Weiner
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Immunology ,Immunology and Allergy - Abstract
Activation of T cells requires both TCR-specific ligation by direct contact with peptide Ag-MHC complexes and coligation of the B7 family of ligands through CD28/CTLA-4 on the T cell surface. We recently reported that coadministration of CD86 cDNA along with DNA encoding HIV-1 Ags i.m. dramatically increased Ag-specific CTL responses. We investigated whether the bone marrow-derived professional APCs or muscle cells were responsible for the enhancement of CTL responses following CD86 coadministration. Accordingly, we analyzed CTL induction in bone marrow chimeras. These chimeras are capable of generating functional viral-specific CTLs against vaccinia virus and therefore represent a useful model system to study APC/T cell function in vivo. In vaccinated chimeras, we observed that only CD86 + Ag + MHC class I results in 1) detectable CTLs following in vitro restimulation, 2) detectable direct CTLs, 3) enhanced IFN-γ production in an Ag-specific manner, and 4) dramatic tissue invasion of T cells. These results support that CD86 plays a central role in CTL induction in vivo, enabling non-bone marrow-derived cells to prime CTLs, a property previously associated solely with bone marrow-derived APCs.
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- 1999
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14. Intracellular adhesion molecule-1 modulates β-chemokines and directly costimulates T cells in vivo
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Devin M. Cunning, Kesen Dang, David B. Weiner, Liesl K. Nottingham, Michael G. Agadjanyan, Ara A. Chalian, Jim Oh, Anthony Tsai, Jong J. Kim, Tzvete Dentchev, Daniel J. Lee, and Lake Morrison
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Cytotoxicity, Immunologic ,Immunogen ,T-Lymphocytes ,Intercellular Adhesion Molecule-1 ,Vascular Cell Adhesion Molecule-1 ,chemical and pharmacologic phenomena ,Biology ,Lymphocyte Activation ,Article ,Interferon-gamma ,Mice ,Adjuvants, Immunologic ,Antigens, CD ,Vaccines, DNA ,Animals ,Humans ,Cytotoxic T cell ,Chemokine CCL4 ,Cell adhesion ,Chemokine CCL3 ,AIDS Vaccines ,CD86 ,Mice, Inbred BALB C ,Membrane Glycoproteins ,Cell adhesion molecule ,CD28 ,T-Lymphocytes, Helper-Inducer ,General Medicine ,Macrophage Inflammatory Proteins ,CD58 Antigens ,Intercellular adhesion molecule ,Molecular biology ,Recombinant Proteins ,Fusion Proteins, gag-pol ,B7-1 Antigen ,HIV-1 ,Female ,B7-2 Antigen - Abstract
The potential roles of adhesion molecules in the expansion of T cell-mediated immune responses in the periphery were examined using DNA immunogen constructs as model antigens. We coimmunized cDNA expression cassettes encoding the adhesion molecules intracellular adhesion molecule-1 (ICAM-1), lymphocyte function associated-3 (LFA-3), and vascular cell adhesion molecule-1 (VCAM-1) along with DNA immunogens, and we analyzed the resulting antigen-specific immune responses. We observed that antigen-specific T-cell responses can be enhanced by the coexpression of DNA immunogen and adhesion molecules ICAM-1 and LFA-3. Coexpression of ICAM-1 or LFA-3 molecules along with DNA immunogens resulted in a significant enhancement of T-helper cell proliferative responses. In addition, coimmunization with pCICAM-1 (and more moderately with pCLFA-3) resulted in a dramatic enhancement of CD8-restricted cytotoxic T-lymphocyte responses. Although VCAM-1 and ICAM-1 are similar in size, VCAM-1 coimmunization did not have any measurable effect on cell-mediated responses. These results suggest that ICAM-1 and LFA-3 provide direct T-cell costimulation. These observations are further supported by the finding that coinjection with ICAM-1 dramatically enhanced the level of interferon-gamma (IFN-gamma) and beta-chemokines macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and regulated on activation normal T-cell expression and secreted (RANTES) produced by stimulated T cells. Through comparative studies, we observed that ICAM-1/LFA-1 T-cell costimulatory pathways are independent of CD86/CD28 pathways and that they may synergistically expand T-cell responses in vivo.
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- 1999
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15. IL-12 Gene as a DNA Vaccine Adjuvant in a Herpes Mouse Model: IL-12 Enhances Th1-Type CD4+ T Cell-Mediated Protective Immunity Against Herpes Simplex Virus-2 Challenge
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Jeong-Im Sin, Jong J. Kim, Renee L. Arnold, Khushroo E. Shroff, Don McCallus, Cathy Pachuk, Sue P. McElhiney, Mary W. Wolf, Sylvia J. Pompa-de Bruin, Terry J. Higgins, Richard B. Ciccarelli, and David B. Weiner
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Immunology ,Immunology and Allergy - Abstract
IL-12 has been shown to enhance cellular immunity in vitro and in vivo. Recent reports have suggested that combining DNA vaccine approach with immune stimulatory molecules delivered as genes may significantly enhance Ag-specific immune responses in vivo. In particular, IL-12 molecules could constitute an important addition to a herpes vaccine by amplifying specific immune responses. Here we investigate the utility of IL-12 cDNA as an adjuvant for a herpes simplex virus-2 (HSV-2) DNA vaccine in a mouse challenge model. Direct i.m. injection of IL-12 cDNA induced activation of resting immune cells in vivo. Furthermore, coinjection with IL-12 cDNA and gD DNA vaccine inhibited both systemic gD-specific Ab and local Ab levels compared with gD plasmid vaccination alone. In contrast, Th cell proliferative responses and secretion of cytokines (IL-2 and IFN-γ) and chemokines (RANTES and macrophage inflammatory protein-1α) were significantly increased by IL-12 coinjection. However, the production of cytokines (IL-4 and IL-10) and chemokine (MCP-1) was inhibited by IL-12 coinjection. IL-12 coinjection with a gD DNA vaccine showed significantly better protection from lethal HSV-2 challenge compared with gD DNA vaccination alone in both inbred and outbred mice. This enhanced protection appears to be mediated by CD4+ T cells, as determined by in vivo CD4+ T cell deletion. Thus, IL-12 cDNA as a DNA vaccine adjuvant drives Ag-specific Th1 type CD4+ T cell responses that result in reduced HSV-2-derived morbidity as well as mortality.
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- 1999
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16. In Vivo Modulation of Vaccine-Induced Immune Responses toward a Th1 Phenotype Increases Potency and Vaccine Effectiveness in a Herpes Simplex Virus Type 2 Mouse Model
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Jean D. Boyer, Jeong-Im Sin, David B. Weiner, Jong J. Kim, Richard B. Ciccarelli, and Terry J. Higgins
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Herpesvirus 2, Human ,medicine.medical_treatment ,Immunology ,Biology ,Antibodies, Viral ,medicine.disease_cause ,Microbiology ,DNA vaccination ,Mice ,Th2 Cells ,Immune system ,Immunity ,Virology ,Vaccines, DNA ,medicine ,Animals ,Mice, Inbred BALB C ,Herpes Genitalis ,Viral Vaccine ,Viral Vaccines ,Th1 Cells ,Interleukin-12 ,Vaccination ,Herpes simplex virus ,Immunization ,Immunoglobulin G ,Insect Science ,Cytokines ,Pathogenesis and Immunity ,Female ,Adjuvant - Abstract
Several vaccines have been investigated experimentally in the herpes simplex virus type 2 (HSV-2) model system. While it is believed that CD4 + -T-cell responses are important for protection in general, the correlates of protection from HSV-2 infection are still under investigation. Recently, the use of molecular adjuvants to drive vaccine responses induced by DNA vaccines has been reported in a number of experimental systems. We sought to take advantage of this immunization model to gain insight into the correlates of immune protection in the HSV-2 mouse model system and to further explore DNA vaccine technology. To investigate whether the Th1- or Th2-type immune responses are more important for protection from HSV-2 infection, we codelivered the DNA expression construct encoding the HSV-2 gD protein with the gene plasmids encoding the Th1-type (interleukin-2 [IL-2], IL-12, IL-15, and IL-18) and Th2-type (IL-4 and IL-10) cytokines in an effort to drive immunity induced by vaccination. We then analyzed the modulatory effects of the vaccine on the resulting immune phenotype and on the mortality and the morbidity of the immunized animals following a lethal challenge with HSV-2. We observed that Th1 cytokine gene coadministration not only enhanced the survival rate but also reduced the frequency and severity of herpetic lesions following intravaginal HSV challenge. On the other hand, coinjection with Th2 cytokine genes increased the rate of mortality and morbidity of the challenged mice. Moreover, of the Th1-type cytokine genes tested, IL-12 was a particularly potent adjuvant for the gD DNA vaccination.
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- 1999
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17. Cytokine Molecular Adjuvants Modulate Immune Responses Induced by DNA Vaccine Constructs for HIV-1 and SIV
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Kenneth A. Simbiri, Jong J. Kim, Michael G. Agadjanyan, Dan Mccallus, Jeong I. Sin, Daniel J. Lee, Rick Ciccarelli, Jim Oh, David B. Weiner, Kesen Dang, Liesl K. Nottingham, Ara A. Chalian, and Tzvete Dentchev
- Subjects
animal diseases ,medicine.medical_treatment ,Genetic Vectors ,Immunology ,Human immunodeficiency virus (HIV) ,Cytomegalovirus ,chemical and pharmacologic phenomena ,HIV Antibodies ,Biology ,Antibodies, Viral ,medicine.disease_cause ,DNA vaccination ,Mice ,chemistry.chemical_compound ,Immune system ,Adjuvants, Immunologic ,In vivo ,Virology ,Vaccines, DNA ,medicine ,Animals ,Humans ,Promoter Regions, Genetic ,Mice, Inbred BALB C ,food and beverages ,Cell Biology ,biochemical phenomena, metabolism, and nutrition ,Fusion Proteins, gag-pol ,Cytokine ,chemistry ,Immunization ,HIV-1 ,Nucleic acid ,Cytokines ,bacteria ,Female ,Simian Immunodeficiency Virus ,DNA - Abstract
DNA or nucleic acid immunization has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. Moreover, immune responses induced by DNA immunization can be enhanced and modulated by the use of molecular adjuvants. To further engineer the immune response in vivo, we investigated the induction and regulation of immune responses from the codelivery of Thl cytokines (interleukin-2 [IL-2] and IL-12), Th2 cytokines (IL-4 and IL-10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes along with a DNA vaccine construct encoding for simian immunodeficiency virus (SIV) gag/pol proteins. We observed that coinjection with IL-2, IL-4, IL-10, and GM-CSF resulted in increased levels of antigen-specific antibodies. In addition, we found that coinjection with cytokine genes drove the immune responses toward a more Thl or Th2 phenotype. We also observed that coadministration of IL-2, IL-12, and GM-CSF genes resulted in a dramatic enhancement of Th proliferation responses. Moreover, coimmunization with IL-12 genes resulted in a dramatic enhancement of antigen-specific cytotoxic T lymphocyte (CTL) responses. These results support the potential utility of molecular adjuvants in DNA vaccine regimens.
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- 1999
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18. Enhancement of protective humoral (Th2) and cell-mediated (Th1) immune responses against herpes simplex virus-2 through co-delivery of granulocyte-macrophage colony-stimulating factor expression cassettes
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David B. Weiner, Richard B. Ciccarelli, Terry J. Higgins, Kenneth E. Ugen, Jeong-Im Sin, and Jong J. Kim
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biology ,Immunology ,T helper cell ,Vaccine efficacy ,Immunoglobulin E ,medicine.disease_cause ,Virology ,DNA vaccination ,Vaccination ,medicine.anatomical_structure ,Herpes simplex virus ,Granulocyte macrophage colony-stimulating factor ,Immune system ,medicine ,biology.protein ,Immunology and Allergy ,medicine.drug - Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) could in theory attract antigen-presenting cells in muscle following intramuscular DNA immunization, resulting in enhanced antigen-specific immune responses. Thus, such adjuvants could constitute an important addition to a herpes vaccine by amplifying specific immune responses. Here we investigate the utility of GM-CSF cDNA as a vaccine adjuvant for herpes simplex virus (HSV)-2 in a mouse challenge model. GM-CSF cDNA co-injection enhanced levels of specific IgG, IgE and IgA against HSV-2 gD protein significantly higher than gD plasmid vaccination alone. Moreover, GM-CSF co-injection induced a dramatic increase in IgG1 levels, as compared to IgG2a levels, suggesting a Th2 bias in the response. T helper cell proliferation and secretion of cytokines (IL-2 and IFN-gamma) were significantly increased by GM-CSF cDNA co-injection. When challenged with a lethal dose of HSV-2, GM-CSF co-injection increased survival rates to 90%, an improvement as compared to gD vaccination alone (60-63%). Furthermore, GM-CSF cDNA co-injection reduced herpetic lesions and resulted in a faster recovery from lesions. These data indicate that GM-CSF cDNA enhances both humoral and cellular immune responses and enhances vaccine efficacy, resulting in reduced HSV-2-derived morbidity as well as mortality.
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- 1998
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19. CD8 positive T cells influence antigen-specific immune responses through the expression of chemokines
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Jean D. Boyer, Jim Oh, Ken Kazahaya, Mosi Bennett, David B. Weiner, Kesen Dang, Tzvete Dentchev, Michael G. Agadjanyan, Yin Hu, Lake Morrison, Liesl K. Nottingham, Anthony Tsai, Jeong I. Sin, Jong J. Kim, Darren M. Wilson, and Ara A. Chalian
- Subjects
Immunogen ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,Mice ,Immune system ,Antigen ,Vaccines, DNA ,Animals ,Cytotoxic T cell ,Chemokine CCL4 ,Chemokine CCL5 ,Macrophage inflammatory protein ,Chemokine CCL3 ,AIDS Vaccines ,Mice, Inbred BALB C ,Interleukin-8 ,Models, Immunological ,Lymphokine ,General Medicine ,Macrophage Inflammatory Proteins ,Th1 Cells ,Acquired immune system ,Chemokine CXCL12 ,Fusion Proteins, gag-pol ,CTL ,Immunology ,HIV-1 ,Female ,Chemokines ,Chemokines, CXC ,T-Lymphocytes, Cytotoxic ,Research Article - Abstract
The potential roles of CD8(+) T-cell-induced chemokines in the expansion of immune responses were examined using DNA immunogen constructs as model antigens. We coimmunized cDNA expression cassettes encoding the alpha-chemokines IL-8 and SDF-1alpha and the beta-chemokines MIP-1alpha, RANTES, and MCP-1 along with DNA immunogens and analyzed the resulting antigen-specific immune responses. In a manner more similar to the traditional immune modulatory role of CD4(+) T cells via the expression of Th1 or Th2 cytokines, CD8(+) T cells appeared to play an important role in immune expansion and effector function by producing chemokines. For instance, IL-8 was a strong inducer of CD4(+) T cells, indicated by strong T helper proliferative responses as well as an enhancement of antibody responses. MIP-1alpha had a dramatic effect on antibody responses and modulated the shift of immune responses to a Th2-type response. RANTES coimmunization enhanced the levels of antigen-specific Th1 and cytotoxic T lymphocyte (CTL) responses. Among the chemokines examined, MCP-1 was the most potent activator of CD8(+) CTL activity. The enhanced CTL results are supported by the increased expression of Th1 cytokines IFN-gamma and TNF-alpha and the reduction of IgG1/IgG2a ratio. Our results support that CD8(+) T cells may expand both humoral and cellular responses in vivo through the elaboration of specific chemokines at the peripheral site of infection during the effector stage of the immune response.
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- 1998
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20. Coadministration of IL-12 or IL-10 Expression Cassettes Drives Immune Responses Toward a Thl Phenotype
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Henry C. Maguire, Anthony Tsai, Liesl K. Nottingham, David B. Weiner, Ara A. Chalian, Jong J. Kim, Jeong I. Sin, and Lake Morrison
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Immunology ,Lymphokine ,Interleukin ,chemical and pharmacologic phenomena ,Cell Biology ,biochemical phenomena, metabolism, and nutrition ,Biology ,Acquired immune system ,Interleukin 10 ,Immune system ,Plasmid ,Immunity ,Virology ,Interleukin 12 ,bacteria - Abstract
Cytokines are important regulators of the immune response. They influence immune expression, the development of immunologic memory, and regulation of antigen-specific and nonspecific immune activation as well as allergic responses. In a model system in mice, we have studied the effect of plasmids expressing interleukin (IL)-10 or IL-12 on the modulation of antigen-specific responses. Coadministration of IL-12 or IL-10 genes with DNA immunogens directed the antigen-specific immune response toward a T helper (Thl)-type immunity. In addition to the modulation of antigen-specific immune responses, we studied the induction of delayedtype hypersensitivity (DTH) to contact allergens as an in vivo model of the Thl response. We found that IL12 and IL-10 gene-containing plasmids, and not the bacterial plasmid alone, upregulate this response. Our cytokine gene delivery technique demonstrates an important level of control of the magnitude and direction of induced immune responses and could be advantageous in...
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- 1998
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21. Modulation of amplitude and direction ofin vivo immune responses by co-administration of cytokine gene expression cassettes with DNA immunogens
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Yin Hu, Nicole K. Doyle, David B. Weiner, Ara A. Chalian, Lake Morrison, Sundarasamy Mahalingam, Kesen Dang, Jean D. Boyer, Neil N. Trivedi, Liesl K. Nottingham, Michael G. Agadjanyan, Anthony Tsai, Michael A. Chattergoon, Jong J. Kim, Lois Ahn, and Darren M. Wilson
- Subjects
biology ,medicine.medical_treatment ,T cell ,Immunology ,chemical and pharmacologic phenomena ,T helper cell ,DNA vaccination ,Immune system ,medicine.anatomical_structure ,Cytokine ,MHC class I ,biology.protein ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,CD8 - Abstract
Immunization with nucleic acids has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. We hypothesize that immunization with DNA could be enhanced by directing specific immune responses induced by the vaccine based on the differential correlates of protection known for a particular pathogen. Recently we and others reported that specific immune responses generated by DNA vaccine could be modulated by co-delivery of gene expression cassettes encoding for IL-12, granulocyte-macrophage colony-stimulating factor and the co-stimulatory molecule CD86. To further engineer the immune response in vivo, we investigated the induction and regulation of immune responses following the co-delivery of pro-inflammatory cytokine (IL-1 alpha, TNF-alpha, and TNF-beta), Th1 cytokine (IL-2, IL-12, IL-15, and IL-18), and Th2 cytokine (IL-4, IL-5 and IL-10) genes. We observed enhancement of antigen-specific humoral response with the co-delivery of Th2 cytokine genes IL-4, IL-5, and IL-10 as well as those of IL-2 and IL-18. A dramatic increase in antigen-specific T helper cell proliferation was seen with IL-2 and TNF-alpha gene co-injections. In addition, we observed a significant enhancement of the cytotoxic response with the co-administration of TNF-alpha and IL-15 genes with HIV-1 DNA immunogens. These increases in CTL response were both MHC class I restricted and CD8+ T cell dependent. Together with earlier reports on the utility of co-immunizing using immunologically important molecules together with DNA immunogens, we demonstrate the potential of this strategy as an important tool for the development of more rationally designed vaccines.
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- 1998
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22. Cardiac Fibroblasts and Arrhythmogenesis
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Jong J. Kim and Nenad Bursac
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business.industry ,Medicine ,business - Published
- 2014
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23. Contributors
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Hugues Abriel, Wayne O. Adkisson, Esperanza Agullo-Pascual, Olujimi A. Ajijola, Amin Al-Ahmad, Oluseun Alli, Robert K. Altman, Elad Anter, Charles Antzelevitch, Justus M.B. Anumonwo, Luciana Armaganijan, Hiroshi Ashikaga, Felipe Atienza, Uma Mahesh R. Avula, Peter H. Backx, Elise Balse, Conor D. Barrett, David G. Benditt, Omer Berenfeld, Donald M. Bers, Charles I. Berul, A. Christian Blank, Raffaella Bloise, Frank Matthias Bogun, Martin Borggrefe, Noel G. Boyle, Günter Breithardt, Marisa Brini, Peter R. Brink, Josep Brugada, Pau Brugada, Pedro Brugada, Ramon Brugada, Victoria Brugada, Eric Buch, Feliksas F. Bukauskas, J. David Burkhardt, Nenad Bursac, Hugh Calkins, David J. Callans, Oscar Campuzano, Sean M. Caples, Ernesto Carafoli, Augustin Castellanos, William Catterall, Marina Cerrone, Lan S. Chen, Lei Chen, Peng-Sheng Chen, Ashley Chin, Aman Chugh, Ira S. Cohen, Stuart J. Connolly, Jason Constantino, Lia Crotti, Frank A. Cuoco, Anne B. Curtis, Ralph J. Damiano, Dawood Darbar, Mithilesh K. Das, Mario Delmar, Eva Delpón, Luigi Di Biase, Sanjay Dixit, Dobromir Dobrev, Derek J. Dosdall, John W. Dyer, Lars Eckardt, Andrew G. Edwards, Igor R. Efimov, Kenneth A. Ellenbogen, Patrick T. Ellinor, Emilia Entcheva, N.A. Mark Estes, Rodolphe Fischmeister, John D. Fisher, Glenn I. Fishman, David S. Frankel, Michael R. Franz, Paul A. Friedman, Victor F. Froelicher, Apoor S. Gami, Alfred L. George, Edward P. Gerstenfeld, Michael R. Gold, Jeffrey J. Goldberger, Eleonora Grandi, Richard A. Gray, William J. Groh, Blair P. Grubb, Michel Haissaguerre, Johan Hake, Henry R. Halperin, Louise Harris, Stéphane Hatem, David L. Hayes, Meleze Hocini, Stefan H. Hohnloser, David Richard Holmes, Masahiko Hoshijima, Yuxuan Hu, Thomas J. Hund, Mathew D. Hutchinson, Hye Jin Hwang, Raymond E. Ideker, Leonard Ilkhanoff, Jodie Ingles, Warren M. Jackman, Pierre Jais, José Jalife, Bong Sook Jhun, Roy M. John, Monique Jongbloed, Mark E. Josephson, Alan H. Kadish, Jérôme Kalifa, Jonathan M. Kalman, Timothy J. Kamp, Mohamed Hani Kanj, Beverly Karabin, Robert S. Kass, Demosthenes G. Katritsis, Kuljeet Kaur, Jong J. Kim, Paulus Kirchhof, André G. Kléber, George J. Klein, Peter Kohl, Aravindan Kolandaivelu, Andrew D. Krahn, Andrew Krumerman, Saurabh Kumar, Karl-Heinz Kuck, Edward G. Lakatta, Rakesh Latchamsetty, Dennis H. Lau, Bruce B. Lerman, Jérôme Leroy, William R. Lewis, Shien-Fong Lin, Mark S. Link, Christopher F. Liu, Deborah J. Lockwood, Peter Loh, Anatoli N. Lopatin, John C. Lopshire, Steven A. Lubitz, Christopher Madias, Aman Mahajan, Jonathan C. Makielski, Marek Malik, Victor A. Maltsev, Francis E. Marchlinski, Ariane J. Marelli, Steven M. Markowitz, Barry J. Maron, Jeffrey R. Martens, Steven O. Marx, Andrew D. McCulloch, Andreas Metzner, Anuska P. Michailova, John Michael Miller, Michelle Lynne Milstein, Peter Mohler, Fred Morady, Robert J. Myerburg, Hiroshi Nakagawa, Carlo Napolitano, Sanjiv M. Narayan, Andrea Natale, Stanley Nattel, Saman Nazarian, Jeanne M. Nerbonne, Fu Siong Ng, Akihiko Nogami, Sami F. Noujaim, Brian Olshansky, Hakan Oral, Jin O-Uchi, Feifan Ouyang, Cevher Ozcan, Douglas L. Packer, Olle Pahlm, Sandeep V. Pandit, David S. Park, Geoffrey S. Pitt, Sunny S. Po, Silvia G. Priori, Wouter-Jan Rappel, Vivek Y. Reddy, Jason O. Robertson, Richard B. Robinson, Dan M. Roden, Robert A. Rose, Michael R. Rosen, Raphael Rosso, Yoram Rudy, Jeremy N. Ruskin, Hani N. Sabbah, Frank B. Sachse, Lindsey L. Saint, Javier Saiz, José A. Sánchez-Chapula, Prashanthan Sanders, Michael C. Sanguinetti, Pasquale Santangeli, Georgia Sarquella-Brugada, Jonathan Satin, Martin Jan Schalij, Benjamin J. Scherlag, Rainer Schimpf, Georg Schmidt, Peter J. Schwartz, Christopher Semsarian, Ashok J. Shah, Robin Shaw, Shey Shing Sheu, Kalyanam Shivkumar, Allan C. Skanes, Virend K. Somers, Bruce S. Stambler, Adam B. Stein, Lynne Warner Stevenson, William G. Stevenson, Jian Sun, Richard Sutton, Michael O. Sweeney, Charles Swerdlow, Juan Tamargo, Harikrishna Tandri, Rabi Tawil, Usha Tedrow, Cecile Terrenoire, Catalina Tobón, Jeffrey A. Towbin, Natalia A. Trayanova, Martin Tristani-Firouzi, Richard G. Trohman, Zian H. Tseng, Mintu P. Turakhia, Ravi Vaidyanathan, Héctor H. Valdivia, Virginijus Valiunas, Marcel A.G. van der Heyden, Christian van der Werf, George F. Van, Marmar Vaseghi, Christian Veltmann, Victoria L. Vetter, Sami Viskin, Niels Voigt, Marc A. Vos, Galen S. Wagner, Paul J. Wang, Rukshen Weerasooriya, Arthur A.M. Wilde, Bruce L. Wilkoff, Erik Wissner, Y. Joseph Woo, Masatoshi Yamazaki, Felix Yang, Yael Yaniv, Sing-Chien Yap, Raymond Yee, Manuel Zarzoso, Katja Zeppenfeld, and Douglas P. Zipes
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- 2014
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24. An HIV Type 2 DNA Vaccine Induces Cross-Reactive Immune Responses against HIV Type 2 and SIV
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David N. Levy, Sagar B. Kudchodkar, David B. Weiner, Michael G. Agadjanyan, Jean D. Boyer, Amy Lin, Mosi Bennett, Neil N. Trivedi, Kenneth E. Ugen, Wilton Levine, and Jong J. Kim
- Subjects
T-Lymphocytes ,T cell ,Immunology ,Cross immunity ,Cross Reactions ,HIV Antibodies ,Biology ,medicine.disease_cause ,Virus ,Cell Line ,DNA vaccination ,Mice ,Mice, Inbred AKR ,Immune system ,Virology ,Chlorocebus aethiops ,Tumor Cells, Cultured ,Vaccines, DNA ,medicine ,Animals ,Humans ,AIDS Vaccines ,Mice, Inbred BALB C ,Vaccines, Synthetic ,Immunogenicity ,virus diseases ,Simian immunodeficiency virus ,Mice, Inbred C57BL ,Infectious Diseases ,medicine.anatomical_structure ,COS Cells ,DNA, Viral ,HIV-2 ,biology.protein ,Female ,Simian Immunodeficiency Virus ,Antibody ,Plasmids - Abstract
We have previously reported on the generation of specific functional immune responses after inoculation of animals with expression vectors encoding HIV-1 genes. This article provides the details of the first application of this new technology to induce immune responses against HIV-2. This virus is molecularly and serologically distinct from HIV-1 and is in fact more closely related to the simian immunodeficiency virus (SIV). Anti-HIV-2 and SIV antibodies were induced in mice of three different haplotypes following a single intramuscular inoculation with an HIV-2/ROD envelope glycoprotein expression vector (pcEnv-2). Boosting of animals with pcEnv-2 induced both anti-HIV-2 neutralizing antibodies and T cell-proliferative responses against HIV-2 and SIVmac proteins. We compared the humoral and cellular immune responses of mice injected with pcEnv-2 and then boosted with either the homologous DNA construct or a recombinant Env protein. Animals boosted with pcEnv-2 generated B and T cell immune responses as strong as those of mice boosted with recombinant gp140 protein in adjuvant. Finally, cellular immune responses were significantly increased with the coadministration of pcEnv-2 and a plasmid expressing interleukin 12. We therefore conclude that DNA plasmid inoculation induces cross-reactive anti-HIV-2 and anti-SIVmac immune responses in mice. This technology should be further investigated as a potential vaccine component for this human pathogen.
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- 1997
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25. DNA gene vaccination for HIV
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David B. Weiner and Jong J. Kim
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Primates ,Combination therapy ,HIV Antigens ,Immunology ,HIV Infections ,Rodentia ,Genome, Viral ,Viral Proteins ,Immune system ,Retrovirus ,Adjuvants, Immunologic ,Acquired immunodeficiency syndrome (AIDS) ,T-Lymphocyte Subsets ,Vaccines, DNA ,medicine ,Animals ,Humans ,AIDS Vaccines ,Clinical Trials as Topic ,Immunity, Cellular ,biology ,Vaccination ,General Medicine ,biology.organism_classification ,medicine.disease ,Antigenic Variation ,Virology ,Regimen ,Antibody Formation ,Lentivirus ,HIV-1 ,Cytokines ,Viral disease - Abstract
The human immunodeficiency virus-1 (HIV-1) is a retrovirus which preferentially infects and kills CD4+ T cells and macrophages, ultimately resulting in immune system failure and multi-pathogen infections. Recent breakthroughs in combination therapy using three different anti-retroviral agents have generated optimism regarding the ability to control viral replication in vivo [46]. However, this therapeutic regimen is costly, and it is too early to tell whether this approach can eradicate established infection [26, 46]. The costs and the stringent administration regimen requirements of these pharmaceutical agents make it clear that these drugs will only be effectively utilized in a limited part of the world population. Therefore, to address the worldwide problem of HIV-1 infection, there remains a need for a prophylactic vaccination strategy designed to control the epidemic through mass immunization campaigns [115].
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- 1997
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26. Development of a multicomponent candidate vaccine for HIV-1
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Michael A. Chattergoon, Jong J. Kim, Bin Wang, Mark L. Bagarazzi, Jean D. Boyer, David B. Weiner, and Velpandi Ayyavoo
- Subjects
chemical and pharmacologic phenomena ,HIV Antibodies ,Biology ,DNA vaccination ,Mice ,Immune system ,Antigen ,Immunity ,Vaccines, DNA ,medicine ,Antigenic variation ,Animals ,AIDS Vaccines ,Acquired Immunodeficiency Syndrome ,Immunity, Cellular ,Mice, Inbred BALB C ,General Veterinary ,General Immunology and Microbiology ,Polyvalent Vaccine ,Immunogenicity ,Public Health, Environmental and Occupational Health ,T-Lymphocytes, Helper-Inducer ,T helper cell ,biochemical phenomena, metabolism, and nutrition ,Virology ,Infectious Diseases ,medicine.anatomical_structure ,DNA, Viral ,Immunology ,HIV-1 ,bacteria ,Molecular Medicine ,Female ,T-Lymphocytes, Cytotoxic - Abstract
Nucleic acid or DNA immunization represents a novel approach to both vaccine and immune therapeutic development. DNA vaccination induces antigen-specific cellular and humoral immune responses through the delivery of non-replicating transcription units which drive the synthesis of specific foreign proteins within the inoculated host. We have previously reported on the potential use of DNA immunization as a novel vaccine strategy for HIV-1. We found that both antigen-specific cellular and humoral immune responses could be induced in vivo with various DNA vaccine constructs against different antigenic targets within HIV-1. In order to enhance the DNA vaccine's ability to elicit cell-mediated immune responses, we co-delivered plasmids encoding costimulatory molecule B7 and interleukin-12 genes with DNA vaccine for HIV-1. We observed a dramatic increase in both antigen-specific T helper cell proliferation and CTL response. Eventual development of successful vaccines for HIV-1 would likely involve targeting multiple antigenic components of the virus to direct and empower the immune system to protect the host from viral infection. We present here the utility of multicomponent DNA immunization to elicit specific humoral and cell-mediated immune responses against different antigenic targets of HIV-1 as well as the ability of this immunization strategy to achieve significant enhancements of antigen-specific cellular immune responses.
- Published
- 1997
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27. Bradycardia alters Ca2+ dynamics enhancing dispersion of repolarization and arrhythmia risk
- Author
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Rita Papp, Robert M. Strongin, Jonathan J. Abramson, Guy Salama, Jong J. Kim, and Jan Němec
- Subjects
Tachycardia ,Bradycardia ,medicine.medical_specialty ,Calcium Channels, L-Type ,Physiology ,Thiazepines ,Action Potentials ,Myocardial Reperfusion ,In Vitro Techniques ,Sodium-Calcium Exchanger ,NAV1.5 Voltage-Gated Sodium Channel ,Plasma Membrane Calcium-Transporting ATPases ,Heart Rate ,Physiology (medical) ,Internal medicine ,Optical mapping ,Dispersion (optics) ,Heart rate ,Medicine ,Repolarization ,Animals ,Calcium Signaling ,Myocardial reperfusion ,Sodium-calcium exchanger ,business.industry ,Cardiac Excitation and Contraction ,Ryanodine Receptor Calcium Release Channel ,Ether-A-Go-Go Potassium Channels ,Sarcoplasmic Reticulum ,Endocrinology ,Gene Expression Regulation ,Cardiology ,cardiovascular system ,Female ,Rabbits ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of repolarization (DOR), and promotes tachyarrhythmias. Yet, the mechanisms responsible for enhanced DOR and tachyarrhythmias remain largely unexplored. Ca2+transients and APs were measured optically from Langendorff rabbit hearts at high (150 × 150 μm2) or low (1.5 × 1.5 cm2) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR = 50 beats/min). Western blots and pharmacological interventions were used to elucidate the regional effects of bradycardia. As a result, bradycardia (SHR 50 beats/min) increased APDs gradually (time constant τf→s= 48 ± 9.2 s) and caused a secondary Ca2+release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 ± 9.7 ms after the Ca2+transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable asynchronous sarcoplasmic reticulum Ca2+release events leading to subcellular Ca2+waves, detectable only at high magnification. SCR was regionally heterogeneous, correlated with APD prolongation ( P < 0.01, n = 5), enhanced DOR ( r = 0.9277 ± 0.03, n = 7), and was gradually reversed by pacing at 120 beats/min along with APD shortening ( P < 0.05, n = 5). A stabilizer of leaky ryanodine receptors (RyR2), 3-(4-benzylcyclohexyl)-1-(7-methoxy-2,3-dihydrobenzo[ f][1,4]thiazepin-4(5 H)-yl)propan-1-one (K201; 1 μM), suppressed SCR and reduced APD at the base, thereby reducing DOR ( P < 0.02, n = 5). Ventricular ectopy induced by bradycardia ( n = 5/15) was suppressed by K201. Western blot analysis revealed spatial differences of voltage-gated L-type Ca2+channel protein (Cav1.2α), Na+-Ca2+exchange (NCX1), voltage-gated Na+channel (Nav1.5), and rabbit ether-a-go-go-related (rERG) protein [but not RyR2 or sarcoplasmic reticulum Ca2+ATPase 2a] that correlate with the SCR distribution and explain the molecular basis for SCR heterogeneities. In conclusion, acute bradycardia elicits synchronized subcellular SCRs of sufficient magnitude to overcome the source-sink mismatch and to promote afterdepolarizations.
- Published
- 2013
28. 401. In Vivo Expression of Plasmid Encoded IgG for PD-1 or LAG3 by Synthetic DNA as a New Tool for Cancer Immunotherapy
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Jong J. Kim, Karuppiah Muthumani, Sagar B. Kudchodkar, Seleeke Flingai, Sangya Agarwal, David B. Weiner, Kenneth E. Ugen, Christopher W. Chung, Ross Plyler, and N.Y. Sardesai
- Subjects
0301 basic medicine ,LAG3 ,medicine.drug_class ,medicine.medical_treatment ,T cell ,Biology ,Monoclonal antibody ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,In vivo ,Drug Discovery ,Genetics ,medicine ,Molecular Biology ,Pharmacology ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Cancer cell ,Cancer research ,biology.protein ,Molecular Medicine ,Antibody - Abstract
Cancers employ various strategies to escape immune surveillance including the exploitation of immune checkpoint inhibitors. Checkpoint inhibitors are receptors found on immune and stromal cells whose function can impact the duration or potency of an immune response. Tumor cells often upregulate ligands for these receptors to protect themselves from the host immune response. Monoclonal antibody (MAb) therapeutics which block checkpoint inhibitor-ligand interactions restore T cell destruction of cancer cells in vivo. MAbs that target the inhibitory T cell signaling mediated by CTLA-4 and/or PD-1 checkpoint inhibitors have recently gained regulatory approval for the treatment of some cancers based on remarkable clinical outcomes.Here we have focused on a new method to improve MAb delivery through direct engineering of MAb in the form of synthetic DNA plasmids. This technology would improve many aspects of such a therapy by lowering cost, increasing in vivo expression times and allowing for simple combination formulations in the absence of a host anti-vector immune response, possibly extending use of these groundbreaking therapies to disadvantaged patient populations. We report that “enhanced and optimized” DNA plasmid technology can be used to direct in vivo production of immunoglobulin heavy and light chains of established monoclonal antibodies which can target the immune checkpoint inhibitors LAG3 and PD-1 as determined in Flow cytometry, ELISA and Western blot assays. Both antibodies are produced at physiologically relevant levels in blood and other tissues of mice using electroporation-enhanced delivery of DNA plasmids encoding genes for each antibody. We report that serum antibodies from inoculated animals retain the ability to bind to their targets and are bioactive in vivo and exhibit immune stimulatory effects for host T cells. These studies have significant implications for prophylactic and therapeutic strategies for cancer and other important diseases and warrants further attention.
- Published
- 2016
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29. Crystallization Kinetics of Nylon 6
- Author
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S.W. Seo and Jong J. Kim
- Subjects
010302 applied physics ,chemistry.chemical_classification ,Range (particle radiation) ,Materials science ,Polymers and Plastics ,Nonisothermal crystallization ,02 engineering and technology ,Polymer ,021001 nanoscience & nanotechnology ,01 natural sciences ,Crystallization kinetics ,chemistry.chemical_compound ,Differential scanning calorimetry ,Nylon 6 ,Chemical engineering ,chemistry ,0103 physical sciences ,Chemical Engineering (miscellaneous) ,0210 nano-technology - Abstract
We have studied the nonisothermal crystallization of nylon 6 polymers using a differential scanning calorimetry technique. Our nylon 6 samples had molecular weights in the range of 11,000-43,000 g/mol (weight average) and polydispersities ( Mw /Mn ) of 1.8-3.0. We evaluated the effects of molecular weight, polydispersity, and moisture content of nylon 6 on the kinetic crystallizability Gc. Because Gc was sensitive to these variables, we concluded that it is an important parameter for understanding the non isothermal crystallization kinetics involved in the solidification of the polymer melt, which takes place in the polymer processing.
- Published
- 1994
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30. Analysis of the potential for HIV-1 Vpr as an anti-cancer agent
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Vance M. Lambert, Jong J. Kim, David B. Weiner, Richard Heller, Niranjan Y. Sardesai, Kenneth E. Ugen, and K. Muthumani
- Subjects
Cell cycle checkpoint ,viruses ,Melanoma ,Electroporation ,Antineoplastic Agents ,vpr Gene Products, Human Immunodeficiency Virus ,Biology ,medicine.disease ,In vitro ,Mice ,Infectious Diseases ,Viral replication ,In vivo ,Apoptosis ,Virology ,Cell Line, Tumor ,Immunology ,Cancer research ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Plasmids - Abstract
Viral protein R (Vpr) is a 14kD, 96 amino acid accessory protein of the HIV virion that has been demonstrated to have important functions in the viral replication cycle including, among others, the induction of cell cycle arrest and apoptosis in rapidly proliferating cells, which results in immune dysfunction in infected individuals. Several investigators have studied the potential use of the apoptosis inducing and cell cycle arrest effect of Vpr as an anti-tumor therapeutic. In vitro studies have indicated that Vpr is cytotoxic against a large number of different tumor cell types including a number that are p53 independent. Likewise, some in vivo tumor studies using different delivery platforms/methods have indicated an anti-cancer effect mediated by Vpr. Our group has used the aggressive and poorly immunogenic murine melanoma tumor line B16.F10 as a model to deliver, through in vivo electroporation, Vpr expressing plasmids to established tumors and have demonstrated that this treatment regimen can induce growth attenuation and tumor regression in a proportion of the treated mice and appears to be associated with the induction of intratumoral apoptosis. Overall, to date, the data from a number of research groups, including our own, have indicated that Vpr has biological activity against a number of tumors in both in vivo and in vitro models and, as such, may be a potential candidate for testing in human clinical trials. In this report, we summarize the evidence supporting this hypothesis.
- Published
- 2009
31. Chemical ablation of the Purkinje system causes early termination and activation rate slowing of long-duration ventricular fibrillation in do
- Author
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Jian Huang, Raymond E. Ideker, Jack M. Rogers, Paul B. Tabereaux, Derek J. Dosdall, Cheryl R. Killingsworth, William M. Smith, Gregory P. Walcott, Peter G. Robertson, and Jong J. Kim
- Subjects
medicine.medical_specialty ,Time Factors ,Heart disease ,Physiology ,Purkinje fibers ,medicine.medical_treatment ,Action Potentials ,In Vitro Techniques ,Purkinje Fibers ,Dogs ,Physiology (medical) ,Internal medicine ,Carnivora ,Medicine ,Animals ,cardiovascular diseases ,Endocardium ,business.industry ,Body Surface Potential Mapping ,Cardiac Pacing, Artificial ,Articles ,Iodides ,medicine.disease ,Ablation ,Electrophysiology ,Disease Models, Animal ,medicine.anatomical_structure ,Ventricular fibrillation ,Circulatory system ,Ventricular Fibrillation ,Cardiology ,cardiovascular system ,Cardiology and Cardiovascular Medicine ,business - Abstract
Endocardial mapping has suggested that Purkinje fibers may play a role in the maintenance of long-duration ventricular fibrillation (LDVF). To determine the influence of Purkinje fibers on LDVF, we chemically ablated the Purkinje system with Lugol solution and recorded endocardial and transmural activation during LDVF. Dog hearts were isolated and perfused, and the ventricular endocardium was exposed and treated with Lugol solution ( n = 6) or normal Tyrode solution as a control ( n = 6). The left anterior papillary muscle endocardium was mapped with a 504-electrode (21 × 24) plaque with electrodes spaced 1 mm apart. Transmural activation was recorded with a six-electrode plunge needle on each side of the plaque. Ventricular fibrillation (VF) was induced, and perfusion was halted. LDVF spontaneously terminated sooner in Lugol-ablated hearts than in control hearts (4.9 ± 1.5 vs. 9.2 ± 3.2 min, P = 0.01). After termination of VF, both the control and Lugol hearts were typically excitable, but only short episodes of VF could be reinduced. Endocardial activation rates were similar during the first 2 min of LDVF for Lugol-ablated and control hearts but were significantly slower in Lugol hearts by 3 min. In control hearts, the endocardium activated more rapidly than the epicardium after 4 min of LDVF with wave fronts propagating most often from the endocardium to epicardium. No difference in transmural activation rate or wave front direction was observed in Lugol hearts. Ablation of the subendocardium hastens VF spontaneous termination and alters VF activation sequences, suggesting that Purkinje fibers are important in the maintenance of LDVF.
- Published
- 2008
32. Complete regression of established subcutaneous B16 murine melanoma tumors after delivery of an HIV-1 Vpr-expressing plasmid by in vivo electroporation
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Kenneth E. Ugen, David B. Weiner, Jong J. Kim, Andrea N. McCray, Karuppiah Muthumani, and Richard Heller
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Electrochemotherapy ,Skin Neoplasms ,Melanoma, Experimental ,Gene Expression ,Apoptosis ,Biology ,Metastasis ,Mice ,Plasmid ,In vivo ,Drug Discovery ,Genetics ,medicine ,Animals ,Molecular Biology ,Pharmacology ,Expression vector ,Electroporation ,Melanoma ,Gene Products, vpr ,Genetic Therapy ,vpr Gene Products, Human Immunodeficiency Virus ,medicine.disease ,Molecular biology ,Mice, Inbred C57BL ,Survival Rate ,HIV-1 ,Molecular Medicine ,Neoplasm Transplantation ,Plasmids - Abstract
Novel therapies and delivery methods directed against malignancies such as melanoma, and particularly metastatic melanoma, are needed. The HIV-1 accessory protein Vpr (viral protein R) has previously been demonstrated to induce G2 cell cycle arrest as well as in vitro growth inhibition/killing of a number of tumor cells by apoptosis. In vivo electroporation has been utilized as an effective delivery method for pharmacologic agents and DNA plasmids that express "therapeutic" proteins and has been targeted to various tissues, including malignant tumors. For the study reported here, we hypothesized that intratumoral delivery of a Vpr expression plasmid through in vivo electroporation would induce apoptosis and growth attenuation or regression of melanoma tumors. Established subcutaneous B16.F10 melanoma tumors were injected intratumorally with a Vpr-expressing (either 25 or 100 microg) plasmid, followed by electroporation, on day 0 (i.e., when tumors had attained an appropriate size) and day 4. Treatment with 25 or 100 microg of the Vpr-expressing plasmid resulted in complete tumor regression with long-term survival in 14.3 and 7.1% of the mice, respectively. In addition, electroporative delivery of the Vpr-expressing plasmid was shown to induce apoptosis in tumors after intratumoral injection. This is the first report demonstrating the ability of Vpr, when delivered as a DNA expression plasmid with in vivo electroporation, to attenuate melanoma lesion growth and induce complete tumor regression coupled with long-term survival of mice in a highly aggressive and metastatic solid tumor model.
- Published
- 2006
33. Optimization of DNA Vaccines Through the Use of Molecular Adjuvants
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David B. Weiner and Jong J. Kim
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Vaccination ,chemistry.chemical_compound ,Immune system ,Immunization ,chemistry ,Antigen ,Nucleic acid ,Transfection ,Biology ,Virology ,DNA ,DNA vaccination - Abstract
Although the injection of DNA into tissues was originally reported in the 1950s, the technology has gained more attention in recent years as a safe means of mimicking in vivo protein production normally associated with natural infection (1-3). Nucleic acid or DNA inoculation is an important vaccination technique that delivers DNA constructs encoding specific immunogens directly into the host (4-11). These expression cassettes transfect the host cells, which become the in vivo protein source for the production of antigen. This antigen then is the focus of the resulting immune response. This vaccination technique is being explored as an immunization strategy against a variety of infectious diseases as well as cancer.
- Published
- 2003
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34. IL-4 increases Simian immunodeficiency virus replication despite enhanced SIV immune responses in infected rhesus macaques
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Jong J. Kim, Kristen Schumann, Jean D. Boyer, David B. Weiner, Brett M. Nath, K Manson, and E Curley
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Cellular immunity ,viruses ,Simian Acquired Immunodeficiency Syndrome ,medicine.disease_cause ,Antibodies, Viral ,Lymphocyte Activation ,Virus Replication ,Virus ,medicine ,Animals ,Humans ,Neutralizing antibody ,biology ,SAIDS Vaccines ,Simian immunodeficiency virus ,Viral Load ,biology.organism_classification ,Virology ,Macaca mulatta ,CD4 Lymphocyte Count ,Infectious Diseases ,Viral replication ,Immunology ,Lentivirus ,biology.protein ,Parasitology ,Immunization ,Simian Immunodeficiency Virus ,Interleukin-4 ,Antibody ,Viral load ,Plasmids - Abstract
It is widely believed that a Th1 type CD4 response is critical for enhancement of CD8 immunity and for controlling HIV-1 infection. Th2 type responses, such as what might be seen in a chronic parasitic infection, would sacrifice cellular immunity and thus benefit the virus at the expense of the host. However, there has been little direct examination of the hypothesis in a primate model system. Accordingly, the simian immunodeficiency virus (SIV) infected rhesus macaque model was used to investigate the impact of immunisation with SIV expressing DNA constructs and co-injection with IL-4 on the SIV specific immunological responses, lymphocyte cell counts, as well as the impact on viral load. IL-4 is a Th2 type cytokine, which enhances antibody production and inhibits a CD4 Th1 phenotype. Rhesus macaques were infected with 10 AID50 of SIVmac239 and treated with 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) 9 weeks post-infection. During PMPA treatment, animals were immunised with plasmids that expressed the SIV proteins, env, rev, gag and pol. In addition, they were immunised with a construct that encoded the gene for IL-4. IL-4 co-immunisation increased the neutralizing antibody titres in this group. Importantly, the viral loads in animals vaccinated with IL-4 expressing plasmid increased during the immunisation regimens despite the higher neutralizing antibody titres. In addition, neutralizing antibodies did not correlate with viral set point prior to PMPA treatment, however, there was a correlation between viral loads and antibody titres following the treatment with PMPA. Antibody titres decreased following the suppression of viral load. Importantly, vaccination in the absence of IL-4 protected CD4 levels without increasing viral load. The data support the hypothesis that inappropriate immune bias toward a Th2 pathway would ultimately enhance disease progression.
- Published
- 2002
35. Modulation of cellular responses by plasmid CD40L: CD40L plasmid vectors enhance antigen-specific helper T cell type 1 CD4+ T cell-mediated protective immunity against herpes simplex virus type 2 in vivo
- Author
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Jong J. Kim, David B. Weiner, Donghui Zhang, and Jeong-Im Sin
- Subjects
medicine.medical_treatment ,T cell ,Herpesvirus 2, Human ,CD40 Ligand ,Genetic Vectors ,Epitopes, T-Lymphocyte ,Lymphocyte Activation ,Injections, Intramuscular ,Epitope ,DNA vaccination ,Mice ,Immune system ,Adjuvants, Immunologic ,Cell Movement ,Genetics ,medicine ,Vaccines, DNA ,Animals ,Humans ,Molecular Biology ,Immunity, Cellular ,Mice, Inbred BALB C ,CD40 ,Herpes Genitalis ,biology ,Th1 Cells ,Acquired immune system ,Cell biology ,Administration, Intravaginal ,Cytokine ,medicine.anatomical_structure ,Immunoglobulin G ,Immunology ,Vagina ,biology.protein ,Molecular Medicine ,Cytokines ,Female ,Chemokines ,CD8 ,Plasmids - Abstract
Engineering gene therapy vectors to modulate the immune response is an important goal. In this regard, costimulation of T cells is a critical determinant in immune activation. The costimulatory molecule CD40, expressed on antigen-presenting cells, is thought to interact with CD40 ligand (CD40L) expressed on activated CD4(+) or CD8(+) T cells to further drive interleukin-2 receptor (IL-2R) expression and antigen-specific T cell expansion necessary for both class II and class I responses. To compare the specific roles of these two costimulatory molecules in immune induction in a herpes simplex virus (HSV) model, we constructed plasmid DNAs expressing CD40 and CD40L, coimmunized these molecules with a gD plasmid vaccine, and then analyzed immune modulatory effects as well as protection against lethal HSV-2 challenge. We observed that gD-specific IgG production was unaffected by these molecules. However, a higher production of IgG2a isotype was induced by CD40L coinjection, suggesting that CD40L drives immune responses towards a helper T cell type 1 (Th1) phenotype. CD40L also enhanced Th cell proliferative responses and production of Th1-type cytokines (IL-2 and IFN-gamma) and beta-chemokines (RANTES and MIP-1alpha) from splenocytes. In contrast, CD40 showed slightly increasing effects on T cell proliferation responses and cytokine and chemokine production. When animals were challenged with a lethal dose of HSV-2, CD40L-coimmunized animals exhibited a significantly enhanced survival rate, as compared with CD40 coinjection or gD DNA vaccine alone. This enhanced protection appears to be mediated by Th1-type CD4(+) T cells, as determined by in vitro and in vivo T cell subset deletion. CD40L also promoted migration of CD4(+) T cells into the muscle sites. These studies demonstrate that CD40L can play an important role in protective antigen-specific immunity in a gene-based model system through increased expansion of the CD4(+) Th1 T cell subset in vivo.
- Published
- 2001
36. DNA Vaccines Encoding Interleukin-8 and RANTES Enhance Antigen-Specific Th1-Type CD4+ T-Cell-Mediated Protective Immunity against Herpes Simplex Virus Type 2 In Vivo
- Author
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Catherine J. Pachuk, C. Satishchandran, David B. Weiner, Jeong-Im Sin, and Jong J. Kim
- Subjects
Chemokine ,Herpesvirus 2, Human ,Immunology ,Herpesvirus Vaccines ,medicine.disease_cause ,Lymphocyte Activation ,Microbiology ,Immunoglobulin G ,DNA vaccination ,Mice ,Immune system ,Th2 Cells ,Immunity ,Virology ,Vaccines and Antiviral Agents ,medicine ,Vaccines, DNA ,Animals ,Macrophage inflammatory protein ,Chemokine CCL5 ,Mice, Inbred BALB C ,biology ,Interleukin-8 ,Chemotaxis ,Viral Vaccines ,Th1 Cells ,Herpes simplex virus ,Insect Science ,biology.protein ,Cytokines ,Female - Abstract
Chemokines are inflammatory molecules that act primarily as chemoattractants and as activators of leukocytes. Their role in antigen-specific immune responses is of importance, but their role in disease protection is unknown. Recently it has been suggested that chemokines modulate immunity along more classical Th1 and Th2 phenotypes. However, no data currently exist in an infectious challenge model system. We analyzed the modulatory effects of selected chemokines (interleukin-8 [IL-8], gamma interferon-inducible protein 10 [IP-10], RANTES, monocyte chemotactic protein 1 [MCP-1], and macrophage inflammatory protein 1α [MIP-1α]) on immune phenotype and protection against lethal challenge with herpes simplex virus type 2 (HSV-2). We observed that coinjection with IL-8 and RANTES plasmid DNAs dramatically enhanced antigen-specific Th1 type cellular immune responses and protection from lethal HSV-2 challenge. This enhanced protection appears to be mediated by CD4+T cells, as determined by in vitro and in vivo T-cell subset deletion. Thus, IL-8 and RANTES cDNAs used as DNA vaccine adjuvants drive antigen-specific Th1 type CD4+T-cell responses, which result in reduced HSV-2-derived morbidity, as well as reduced mortality. However, coinjection with DNAs expressing MCP-1, IP-10, and MIP-1α increased mortality in the challenged mice. Chemokine DNA coinjection also modulated its own production as well as the production of cytokines. These studies demonstrate that chemokines can dominate and drive immune responses with defined phenotypes, playing an important role in the generation of protective antigen-specific immunity.
- Published
- 2000
37. Chemokine gene adjuvants can modulate immune responses induced by DNA vaccines
- Author
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Joo-S. Yang, Jong J. Kim, David B. Weiner, Tzvete Dentchev, and Kesen Dang
- Subjects
Chemokine ,Immunology ,Gene Expression ,chemical and pharmacologic phenomena ,Lymphocyte Activation ,Proinflammatory cytokine ,DNA vaccination ,Mice ,Immune system ,Virology ,Vaccines, DNA ,Macrophage ,Animals ,Chemokine CCL4 ,Chemokine CCL5 ,Chemokine CCL3 ,CD86 ,Mice, Inbred BALB C ,biology ,Interleukin-8 ,CCL18 ,Cell Biology ,T-Lymphocytes, Helper-Inducer ,Macrophage Inflammatory Proteins ,Antibody Formation ,biology.protein ,Cytokines ,Tumor necrosis factor alpha ,Female ,Immunization ,Chemokines ,T-Lymphocytes, Cytotoxic - Abstract
Nucleic acid immunization has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. Moreover, immune responses induced by DNA immunization can be enhanced by the use of molecular adjuvants. For example, coadministration of costimulatory molecules (CD80 and CD86), proinflammatory cytokines (interleukin-1alpha [IL-1alpha], tumor necrosis factor-alpha [TNF-alpha, and TNF-beta), Th1 cytokines (interleukin-2 [IL-2], IL-12, IL-15, and IL-18), Th2 cytokines (IL-4, IL-5, and IL-10), and granulocytes-macrophage colony-stimulating factor (GM-CSF) with DNA vaccine constructs leads to modulation of the magnitude and direction (humoral or cellular) of the immune responses. To further engineer the immune response in vivo, we compared the induction and regulation of immune responses from the codelivery of chemokine (IL-8, interferon-gamma-inducible protein-10 [gammaIP-10], macrophage inhibitory protein-1alpha [MIP-1alpha], and RANTES) genes with codelivery of cytokine genes. We found that as in cytokine gene codelivery, coimmunization with chemokine genes along with DNA immunogen constructs can modulate the direction and magnitude of induced immune responses. We observed that coimmunization with IL-8, gammaIP-10, and MIP-1alpha genes increased the antibody response. We also found that coinjection with IL-8, gammaIP-10, and RANTES resulted in a dramatic enhancement of T helper (Th) proliferation response. Furthermore, among all coinjection combinations, we found that RANTES coinjection caused a high level of cytotoxic lymphocyte (CTL) enhancement. This enhancement of CTL responses observed from the coinjection with RANTES was CD8+ T cell dependent. Together with earlier reports on the utility of coimmunizing immunologically important molecules with DNA immunogens, we demonstrate the potential of this strategy as an important tool for the development of more rationally designed vaccines.
- Published
- 2000
38. Modulation of antigen-specific humoral responses in rhesus macaques by using cytokine cDNAs as DNA vaccine adjuvants
- Author
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Michael S. Wyand, Daniel J. Lee, David B. Weiner, Jean D. Boyer, Kenneth E. Ugen, Joo-Sung Yang, Jong J. Kim, Kelledy Manson, and Thomas C. VanCott
- Subjects
Interleukin 2 ,DNA, Complementary ,Immunology ,Biology ,medicine.disease_cause ,Antibodies, Viral ,Microbiology ,DNA vaccination ,Immune system ,Antigen ,Adjuvants, Immunologic ,Virology ,Vaccines and Antiviral Agents ,medicine ,Animals ,Humans ,Antigens, Viral ,Viral Vaccine ,Viral Vaccines ,Simian immunodeficiency virus ,biology.organism_classification ,Macaca mulatta ,Rhesus macaque ,Insect Science ,biology.protein ,Cytokines ,Antibody ,medicine.drug - Abstract
An important limitation of DNA immunization in nonhuman primates is the difficulty in generating high levels of antigen-specific antibody responses; strategies to enhance the level of immune responses to DNA immunization may be important in the further development of this vaccine strategy for humans. We approached this issue by testing the ability of molecular adjuvants to enhance the levels of immune responses generated by multicomponent DNA vaccines in rhesus macaques. Rhesus macaques were coimmunized intramuscularly with expression plasmids bearing genes encoding Th1 (interleukin 2 [IL-2] and gamma interferon)- or Th2 (IL-4)-type cytokines and DNA vaccine constructs encoding human immunodeficiency virus Env and Rev and simian immunodeficiency virus Gag and Pol proteins. We observed that the cytokine gene adjuvants (especially IL-2 and IL-4) significantly enhanced antigen-specific humoral immune responses in the rhesus macaque model. These results support the assumption that antigen-specific responses can be engineered to a higher and presumably more desirable level in rhesus macaques by genetic adjuvants.
- Published
- 2000
39. Macrophage colony-stimulating factor can modulate immune responses and attract dendritic cells in vivo
- Author
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Anthony Tsai, Jong J. Kim, Lake Morrison, Jim Oh, David B. Weiner, Joo-Sung Yang, Jeong I. Sin, Kesen Dang, Daniel J. Lee, Liesl K. Nottingham, Ara A. Chalian, Darren M. Wilson, Tzvete Dentchev, and Michael G. Agadjanyan
- Subjects
Macrophage colony-stimulating factor ,Immunogen ,T cell ,Genetic Vectors ,Cytomegalovirus ,chemical and pharmacologic phenomena ,Biology ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,DNA vaccination ,Mice ,Immune system ,Granulocyte Colony-Stimulating Factor ,Genetics ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Promoter Regions, Genetic ,Molecular Biology ,Mice, Inbred BALB C ,Macrophage Colony-Stimulating Factor ,Muscles ,Granulocyte-Macrophage Colony-Stimulating Factor ,Dendritic cell ,Dendritic Cells ,Flow Cytometry ,Interleukin-12 ,CTL ,medicine.anatomical_structure ,Chemokines, CC ,Immunology ,HIV-1 ,Molecular Medicine ,Female ,Interleukin-4 ,Lymphoproliferative response ,Plasmids ,T-Lymphocytes, Cytotoxic - Abstract
Studies have indicated that professional APCs in the periphery, such as dendritic cells and macrophages, play an important role in initiating DNA vaccine-specific immune responses. To engineer the immune response induced by DNA vaccines in vivo we investigated the modulatory effects of codelivering growth factor genes for the hematopoietic APCs along with DNA vaccines. Specifically, we examined the effects on the antigen-specific immune responses following the codelivery of the gene expression cassettes for M-CSF, G-CSF, and GM-CSF along with HIV-1 DNA immunogen constructs. We observed that coimmunization with GM-CSF increased the antibody response and resulted in a significant enhancement of lymphoproliferative response. Furthermore, among all coinjection combinations, we found that M-CSF coinjections resulted in a high level of CTL enhancement. This enhancement of CTL responses observed from the coinjection with M-CSF was CD8+ T cell dependent and was associated with the presence of CD11c+ cells at the site of injection and with the antigen-specific induction of the beta-chemokine MIP-1beta, suggesting a role for this chemokine in CTL induction. These results suggest that hematopoietic growth factors should be further studied as potential adjuvants for in vivo modulators of immune responses.
- Published
- 2000
40. Engineering DNA vaccines via co-delivery of co-stimulatory molecule genes
- Author
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David B. Weiner, Darren M. Wilson, Michael G. Agadjanyan, Lake Morrison, Jong J. Kim, Ara A. Chalian, Ali Javadian, Mark L. Bagarazzi, Liesl K. Nottingham, and Anthony Tsai
- Subjects
DNA, Complementary ,Pan troglodytes ,HIV Antigens ,Molecular Sequence Data ,chemical and pharmacologic phenomena ,Biology ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,DNA vaccination ,law.invention ,Epitopes ,Mice ,Immune system ,law ,Antigens, CD ,MHC class I ,Vaccines, DNA ,Animals ,Amino Acid Sequence ,Cloning, Molecular ,Antigen Presentation ,Lymphokines ,Mice, Inbred BALB C ,Membrane Glycoproteins ,General Veterinary ,General Immunology and Microbiology ,Immunogenicity ,Histocompatibility Antigens Class I ,Public Health, Environmental and Occupational Health ,T-Lymphocytes, Helper-Inducer ,Virology ,CTL ,Infectious Diseases ,Immunization ,Immunology ,biology.protein ,Recombinant DNA ,B7-1 Antigen ,HIV-1 ,Molecular Medicine ,B7-2 Antigen ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
DNA immunization has been investigated as a potential immunization strategy against infectious diseases and cancer. To enhance a DNA vaccine's ability to induce CTL response in vivo, we co-administered CD80 and CD86 expression cassettes along with HIV-1 immunogens. This manipulation resulted in a dramatic increase in MHC class I-restricted and CD8+ T-cell-dependent CTL responses in both mice and chimpanzees. This strategy of engineering vaccine producing cells to be more efficient T-cell activators could be an important tool for optimizing antigen-specific T-cell-mediated immune responses in the pursuit of more rationally designed vaccines and immune therapies.
- Published
- 1998
41. DNA gene vaccination for HIV
- Author
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Jong J. Kim and David B. Weiner
- Published
- 1998
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42. STIM1-Ca2+ signaling modulates automaticity of the mouse sinoatrial node.
- Author
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Hengtao Zhang, Sun, Albert Y., Jong J. Kim, Graham, Victoria, Finch, Elizabeth A., Nepliouev, Igor, Guiling Zhao, Tianyu Li, Lederer, W. J., Stiber, Jonathan A., Pitt, Geoffrey S., Bursac, Nenad, and Rosenberg, Paul B.
- Subjects
CARDIAC pacemakers ,HEART cells ,SINOATRIAL node ,SARCOPLASMIC reticulum ,CHOLINERGIC mechanisms - Abstract
Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca
2+ release from internal Ca2+ stores (Ca2+ clock) to adjust heart rate to meet hemodynamic demand. Here, we report that stromal interaction molecule 1 (STIM1) and Orai1 channels, key components of store-operated Ca2+ entry, are selectively expressed in SANCs. Cardiac-specific deletion of STIM1 in mice resulted in depletion of sarcoplasmic reticulum (SR) Ca2+ stores of SANCs and led to SAN dysfunction, as was evident by a reduction in heart rate, sinus arrest, and an exaggerated autonomic response to cholinergic signaling. Moreover, STIM1 influenced SAN function by regulating ionic fluxes in SANCs, including activation of a store-operated Ca2+ current, a reduction in L-type Ca2+ current, and enhancing the activities of Na+/Ca2+ exchanger. In conclusion, these studies reveal that STIM1 is a multifunctional regulator of Ca2+ dynamics in SANCs that links SR Ca2+ store content with electrical events occurring in the plasma membrane, thereby contributing to automaticity of the SAN. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
43. In vivo engineering of a cellular immune response by co-administration of IL-12 expression vector with a DNA immunogen
- Author
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David B. Weiner, Jean D. Boyer, Velpandi Ayyavoo, Michael A. Chattergoon, Bin Wang, Kesan Dang, Jong J. Kim, and Mark L. Bagarazzi
- Subjects
Expression vector ,Immune system ,Immunogen ,In vivo ,Immunology ,Interleukin 12 ,Immunology and Allergy ,A-DNA ,Biology ,Co administration - Published
- 1997
- Full Text
- View/download PDF
44. Improved Behavioral Recovery Following Intravenous Administration of Human Umbilical Cord Blood Cells in Rats with Spinal Cord Injury
- Author
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Eugene S. Fu, Alison E. Willing, Jong J. Kim, Samuel Saporta, and Lucy O. Colina
- Subjects
Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,business.industry ,Anesthesia ,Medicine ,business ,medicine.disease ,Umbilical cord ,Spinal cord injury - Published
- 2002
- Full Text
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45. Methylprednisolone Inhibits Cytokine Production in the Spinal Cord Following Compression Injury in Rats
- Author
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Eugene S. Fu, Jong J. Kim, and Samuel Saporta
- Subjects
Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Cytokine ,Methylprednisolone ,business.industry ,Anesthesia ,medicine.medical_treatment ,medicine ,Spinal cord ,business ,Compression injury ,medicine.drug - Published
- 2002
- Full Text
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46. ACQUIRED LQT2 LEADS TO MARKED SPATIAL HETEROGENEITY (SH) OF CA2+ TRANSIENT
- Author
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Jan Nemec, Guy Salama, and Jong J. Kim
- Subjects
business.industry ,Biophysics ,Medicine ,Transient (oscillation) ,Cardiology and Cardiovascular Medicine ,business ,Spatial heterogeneity - Full Text
- View/download PDF
47. Enhancing geomechanical characteristics of calcium sulfoaluminate (CSA) cement-treated soil under low confining pressures.
- Author
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Ocheme JI, Kim J, and Moon SW
- Abstract
This study examines the efficacy of employing calcium sulfoaluminate (CSA) cement, an environmentally friendly binder, for enhancing the geomechanical characteristics of sand, particularly under low confining pressure conditions. A series of triaxial consolidated drained tests were performed on sand samples treated with varying content (5, 7, and 10%) of CSA cement and 10% ordinary Portland cement (OPC) under various low confining pressures (50, 100, 200, and 400 kPa). The test findings demonstrated the importance of cement content and confining pressure on the mode of failure, stress-strain and volumetric behavior, failure characteristics, and shear strength parameters of the treated quartz sand. After a curing period of 14 days, samples treated with 10% CSA cement exhibited a remarkable 212% increase in peak deviator stress and an 89% reduction in axial strain at failure, indicating higher initial stiffness compared to untreated samples under a 400 kPa confining pressure. Furthermore, the samples treated with 10% CSA exhibited higher peak deviator stress, initial stiffness, and strength development compared to those treated with 10% OPC. The scanning electron microscopy analysis provides insights into particle breakage and bond degradation processes, which increase with confining pressure in CSA-treated samples. Also, the mode of failure analysis reveals a transition from ductile to slightly brittle behavior with increasing cement content. Notably, the geomechanical properties of the treated material emphasized the significant impact of CSA cement on soil improvement. Thus offering a sustainable alternative for soil improvement in construction projects., (© 2024. The Author(s).)
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- 2024
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48. Stability of soil slope in Almaty covered with steel slag under the effect of rainfall.
- Author
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Abishev R, Satyanaga A, Pernebekova G, Rahardjo H, Zhai Q, Shon CS, Moon SW, and Kim J
- Abstract
The issue of rainfall-induced slope failure has attracted more attention from geotechnical engineers as a consequence of global warming. Current cumulative waste disposal has generated scientific interest in the utilization of waste materials in geotechnical design for climate change adaptation measures. Taking into consideration the effect of slope height and angle, steel slag-a waste product derived from the production of steel-was investigated as a slope cover against rainfall. To assess the stability of the slope and the infiltration of water into the soil, numerical analyses were conducted using both SEEP/W and SLOPE/W software in conjunction with rainfall conditions. Based on the findings, it can be concluded that increasing the slope's elevation and inclination will have an adverse effect on its safety factor. Steel slag can nevertheless be utilized for minimizing rainwater infiltration into the slope, as indicated by the pore-water pressure variations and graphs of the safety factor versus time. For a 20-m slope height, steel slag slopes have demonstrated a lower factor of safety difference in comparison to the initial slope without remediation. Regardless of slope angle and slope height, the safety factor reduces marginally during rainfall., (© 2024. The Author(s).)
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- 2024
- Full Text
- View/download PDF
49. YAP induces a neonatal-like pro-renewal niche in the adult heart.
- Author
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Li RG, Li X, Morikawa Y, Grisanti-Canozo FJ, Meng F, Tsai CR, Zhao Y, Liu L, Kim J, Xie B, Klysik E, Liu S, Samee MAH, and Martin JF
- Abstract
After myocardial infarction (MI), mammalian hearts do not regenerate, and the microenvironment is disrupted. Hippo signaling loss of function with activation of transcriptional co-factor YAP induces heart renewal and rebuilds the post-MI microenvironment. In this study, we investigated adult renewal-competent mouse hearts expressing an active version of YAP, called YAP5SA, in cardiomyocytes (CMs). Spatial transcriptomics and single-cell RNA sequencing revealed a conserved, renewal-competent CM cell state called adult (a)CM2 with high YAP activity. aCM2 co-localized with cardiac fibroblasts (CFs) expressing complement pathway component C3 and macrophages (MPs) expressing C3ar1 receptor to form a cellular triad in YAP5SA hearts and renewal-competent neonatal hearts. Although aCM2 was detected in adult mouse and human hearts, the cellular triad failed to co-localize in these non-renewing hearts. C3 and C3ar1 loss-of-function experiments indicated that C3a signaling between MPs and CFs was required to assemble the pro-renewal aCM2, C3+ CF and C3ar1+ MP cellular triad.
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- 2024
- Full Text
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50. Application of foam assisted water-alternating-gas flooding and quantification of resistivity and water saturation by experiment and simulation to determine foam propagation in sandstone.
- Author
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Khan JA, Kim J, Irawan S, Permatasar KA, Verdin PG, Cai B, and Yekeen N
- Abstract
Foam flooding by Foam Assisted Water-Alternating-Gas (FAWAG) is an important enhanced oil recovery method that has proven successful in experimental and pilot studies. The present study is carried out to monitor the movement of the foam front once injected into the porous medium. This study aims to investigate applications of resistivity waves to monitor foam propagation in a sandstone formation. In the present lab-scale experiments and simulations, resistivity measurements were carried out to monitor the progression of foam in a sand pack, and the relationships between foam injection time and resistivity, as well as brine saturation, were studied. The brine saturation from foam simulation using CMG STAR is exported to COMSOL and calculated true formation resistivity. A diagram was produced summarizing the progression of foam through the sand pack in the function of time, which enabled us to establish how foam progressed through a porous medium. A surfactant and brine mixture was injected into the sand pack, followed by nitrogen gas to generate the foam in situ. As foam progressed through the sand pack, resistance measurements were taken in three zones of the sand pack. The resistance was then converted into resistivity and finally into brine saturation. As foam travels through the sand pack, it is predicted to displace the brine initially in place. This gradually increases each zone's resistivity (decreases the brine saturation) by displacing the brine. Also, an increase in the surfactant concentration results in higher resistivity. Finally, a comparison of three different surfactant concentrations was evaluated in terms of resistivity results, water saturation, and foam propagation monitoring to obtain the optimum surfactant concentration involved in foam flooding., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)
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- 2024
- Full Text
- View/download PDF
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