23 results
Search Results
2. Immunogenicity and Cross Protection in Mice Afforded by Pandemic H1N1 Live Attenuated Influenza Vaccine Containing Wild-Type Nucleoprotein.
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Rekstin, Andrey, Isakova-Sivak, Irina, Petukhova, Galina, Korenkov, Daniil, Losev, Igor, Smolonogina, Tatiana, Tretiak, Tatiana, Donina, Svetlana, Shcherbik, Svetlana, Bousse, Tatiana, and Rudenko, Larisa
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PREVENTION of epidemics , *INFLUENZA prevention , *ANIMAL experimentation , *ANTIGENS , *BIOLOGICAL assay , *DYNAMICS , *ENZYME-linked immunosorbent assay , *FLOW cytometry , *GENETIC techniques , *GLYCOSIDASES , *IMMUNOGLOBULINS , *IMMUNOLOGICAL adjuvants , *INFLUENZA vaccines , *MICE , *NUCLEIC acids , *PROBABILITY theory , *PROTEINS , *RESEARCH funding , *T cells , *TOXICITY testing , *DRUG development , *INFLUENZA A virus, H1N1 subtype , *DATA analysis software , *DESCRIPTIVE statistics , *IN vitro studies , *MANN Whitney U Test , *KRUSKAL-Wallis Test , *IN vivo studies - Abstract
Since conserved viral proteins of influenza virus, such as nucleoprotein (NP) and matrix 1 protein, are the main targets for virus-specific CD8+ cytotoxic T-lymphocytes (CTLs), we hypothesized that introduction of the NP gene of wild-type virus into the genome of vaccine reassortants could lead to better immunogenicity and afford better protection. This paper describes in vitro and in vivo preclinical studies of two new reassortants of pandemic H1N1 live attenuated influenza vaccine (LAIV) candidates. One had the hemagglutinin (HA) and neuraminidase (NA) genes from A/South Africa/3626/2013 H1N1 wild-type virus on the A/Leningrad/134/17/57 master donor virus backbone (6 : 2 formulation) while the second had the HA, NA, and NP genes of the wild-type virus on the same backbone (5 : 3 formulation). Although both LAIVs induced similar antibody immune responses, the 5 : 3 LAIV provoked greater production of virus-specific CTLs than the 6 : 2 variant. Furthermore, the 5 : 3 LAIV-induced CTLs had higher in vivo cytotoxic activity, compared to 6 : 2 LAIV. Finally, the 5 : 3 LAIV candidate afforded greater protection against infection and severe illness than the 6 : 2 LAIV. Inclusion in LAIV of the NP gene from wild-type influenza virus is a new approach to inducing cross-reactive cell-mediated immune responses and cross protection against pandemic influenza. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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3. Embargoed - Researchers devise novel solution to preventing relapse after CAR T-cell therapy.
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CHIMERIC antigen receptors ,CYTOKINE release syndrome ,T cells ,BLOOD proteins ,IMMUNOLOGIC memory - Abstract
Researchers at the Dana-Farber Cancer Institute have developed a technique to prevent relapse after CAR T-cell therapy, a breakthrough treatment for certain forms of cancer. The technique, called CAR-Enhancer (CAR-E), spurs CAR T cells to be more active and persist longer in the body, allowing them to eliminate all tumor cells and form a memory of the cancer. In laboratory and animal studies, CAR-E therapy successfully eradicated tumor cells, paving the way for future clinical trials. The researchers hope that CAR-E therapy can be easily integrated into the care of patients receiving CAR T-cell therapies. [Extracted from the article]
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- 2024
4. Combinatorial targeting of multiple myeloma by complementing T cell engaging antibody fragments.
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Geis, Maria, Nowotny, Boris, Bohn, Marc-Dominic, Kouhestani, Dina, Einsele, Hermann, Bumm, Thomas, and Stuhler, Gernot
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T cells ,IMMUNOGLOBULINS ,MULTIPLE myeloma ,ANTIGENS ,IMMUNOTHERAPY - Abstract
Bispecific T cell engaging antibodies (BiTEs) address tumor associated antigens that are over-expressed on cancer but that can also be found on healthy tissues, causing substantial on-target/off-tumor toxicities. To overcome this hurdle, we recently introduced hemibodies, a pair of complementary antibody fragments that redirect T cells against cancer-defining antigen combinations. Here we show that hemibodies addressing CD38 and SLAMF7 recruit T cells for the exquisite elimination of dual antigen positive multiple myeloma cells while leaving single antigen positive bystanders unharmed. Moreover, CD38 and SLAMF7 targeting BiTEs, but not hemibodies induce massive cytokine release and T cell fratricide reactions, a major drawback of T cell recruiting strategies. Together, we provide evidence in vitro and in vivo that hemibodies can be developed for the effective and highly specific immunotherapy of multiple myeloma. Geis et al. investigate the potential application of hemibodies, a pair of complementary antibody fragments that redirect T cells against cancer-defining antigen combinations, such as CD38 and SLAMF7, to target multiple myeloma. Their study provides evidence that hemibodies can be developed for effective immunotherapy against multiple myeloma. [ABSTRACT FROM AUTHOR]
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- 2021
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5. The Potential Role of Regulatory B Cells in Idiopathic Membranous Nephropathy.
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Dong, Zhaocheng, Liu, Zhiyuan, Dai, Haoran, Liu, Wenbin, Feng, Zhendong, Zhao, Qihan, Gao, Yu, Liu, Fei, Zhang, Na, Dong, Xuan, Zhou, Xiaoshan, Du, Jieli, Huang, Guangrui, Tian, Xuefei, and Liu, Baoli
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REGULATORY B cells ,HUMORAL immunity ,KIDNEY diseases ,T cells ,HUMAN body ,KIDNEY glomerulus diseases ,CYTOKINES ,AUTOANTIBODIES ,IMMUNOGLOBULINS ,ANIMAL experimentation ,ARTHRITIS Impact Measurement Scales ,IMMUNOLOGY technique ,CELL communication ,PSYCHOLOGICAL tests ,DISEASE susceptibility ,IMMUNITY ,GLOMERULONEPHRITIS ,PSYCHOLOGICAL adaptation ,ANTIGENS - Abstract
Regulatory B cells (Breg) are widely regarded as immunomodulatory cells which play an immunosuppressive role. Breg inhibits pathological autoimmune response by secreting interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and adenosine and through other ways to prevent T cells and other immune cells from expanding. Recent studies have shown that different inflammatory environments induce different types of Breg cells, and these different Breg cells have different functions. For example, Br1 cells can secrete IgG4 to block autoantigens. Idiopathic membranous nephropathy (IMN) is an autoimmune disease in which the humoral immune response is dominant and the cellular immune response is impaired. However, only a handful of studies have been done on the role of Bregs in this regard. In this review, we provide a brief overview of the types and functions of Breg found in human body, as well as the abnormal pathological and immunological phenomena in IMN, and propose the hypothesis that Breg is activated in IMN patients and the proportion of Br1 can be increased. Our review aims at highlighting the correlation between Breg and IMN and proposes potential mechanisms, which can provide a new direction for the discovery of the pathogenesis of IMN, thus providing a new strategy for the prevention and early treatment of IMN. [ABSTRACT FROM AUTHOR]
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- 2020
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6. Kyverna Therapeutics Congratulates Prof. G. Schett et al. on the Publication of a Case Series Follow-up of 15 Patients Living with Autoimmune Disease Treated With CAR T-Cell Therapy.
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AUTOIMMUNE diseases ,THERAPEUTICS ,T cells ,THERAPEUTIC use of proteins - Abstract
Kyverna Therapeutics, a biopharmaceutical company focused on developing cell therapies for autoimmune diseases, congratulates Prof. Georg Schett and his team on the publication of a case series in the New England Journal of Medicine. The study reports on 15 patients with severe autoimmune diseases who received a single infusion of autologous CD19 chimeric antigen receptor (CAR) T cells. After treatment, all patients were able to discontinue immunosuppressive therapy, and the treatment was well tolerated with mild side effects. This research offers hope for patients with autoimmune diseases and paves the way for further clinical studies on CAR T-cell therapies. [Extracted from the article]
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- 2024
7. Granzyme B induced by Rv0140 antigen discriminates latently infected from active tuberculosis individuals.
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Ouni, Rym, Gharsalli, Houda, Dirix, Violette, Braiek, Amani, Sendi, Nadia, Jarraya, Afifa, Douik El Gharbi, Leila, Barbouche, Mohamed‐Ridha, and Benabdessalem, Chaouki
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T cells ,ANTIGENS ,SECRETION ,PREVENTIVE medicine ,IMMUNOGLOBULINS ,TUBERCULOSIS - Abstract
Nearly two billion people are latently infected with Mtb (LTBI). Detection of LTBI with high risk to develop active tuberculosis (aTB) is considered the cornerstone to control the disease. The current challenge is to identify markers that better classify LTBI versus aTB. It has been previously shown that Rv0140, a reactivation‐associated antigen of Mtb, induces significantly higher IFN‐γ production in LTBI individuals as compared to aTB patients. Herein, we show that Rv0140 induces high granzyme B level by PBMCs derived from LTBI (n = 34) as compared to aTB (n = 18). Receiving operator characteristic (ROC) curves were used to evaluate the capacity of Rv0140 to discriminate between LTBI and aTB by measuring IFN‐γ and granzyme B secretion. Our results show that, in response to Rv0140, granzyme B seems to allow better discrimination of LTBI from aTB with areas under the curve (AUC) of 0.88 (95% CI 0.79–0.98) as compared to IFN‐γ with AUC of 0.85 (95% CI 0.74–0.96) even though CI overlap. Intracellular staining (ICS) experiments and the use of anti‐MHC I antibody showed that granzyme B is mainly produced by CD8+ T cells in response to Rv0140. Thus, we propose granzyme B as a host marker to help identify LTBI individuals. Rv0140‐induced Granzyme B biomarker discriminates TB infection status [ABSTRACT FROM AUTHOR]
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- 2019
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8. Allergen-Specific Antibodies Regulate Secondary Allergen-Specific Immune Responses.
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Eckl-Dorna, Julia, Villazala-Merino, Sergio, Linhart, Birgit, Karaulov, Alexander V., Zhernov, Yury, Khaitov, Musa, Niederberger-Leppin, Verena, and Valenta, Rudolf
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ALLERGENS ,IMMUNOGLOBULINS ,T cells ,IMMUNOGLOBULIN E ,ANTIGENS - Abstract
Immunoglobulin E (IgE)-associated allergy is the most common immunologically-mediated hypersensensitivity disease. It is based on the production of IgE antibodies and T cell responses against per se innocuous antigens (i.e., allergens) and subsequent allergen-induced inflammation in genetically pre-disposed individuals. While allergen exposure in sensitized subjects mainly boosts IgE production and T cell activation, successful allergen-specific immunotherapy (AIT) induces the production of allergen-specific IgG antibodies and reduces T cell activity. Under both circumstances, the resulting allergen-antibody complexes play a major role in modulating secondary allergen-specific immune responses: Allergen-IgE complexes induce mast cell and basophil activation and perpetuate allergen-specific T cell responses via presentation of allergen by allergen presenting cells to T cells, a process called IgE-facilitated antigen presentation (FAP). In addition, they may induce activation of IgE memory B cells. Allergen-induced production of specific IgGs usually exerts ameliorating effects but under certain circumstances may also contribute to exacerbation. Allergen-specific IgG antibodies induced by AIT which compete with IgE for allergen binding (i.e., blocking IgG) inhibit formation of IgE-allergen complexes and reduce activation of effector cells, B cells and indirectly T cells as FAP is prevented. Experimental data provide evidence that by binding of allergen-specific IgG to epitopes different from those recognized by IgE, allergen-specific IgG may enhance IgE-mediated activation of mast cells, basophils and allergen-specific IgE
+ B cells. In this review we provide an overview about the role of allergen-specific antibodies in regulating secondary allergen-specific immune responses. [ABSTRACT FROM AUTHOR]- Published
- 2019
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9. Unregulated antigen-presenting cell activation by T cells breaks self tolerance.
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Jaeu Yi, Jisun Jung, Sung-Wook Hong, Jun Young Lee, Daehee Han, Kwang Soon Kim, Sprent, Jonathan, and Surh, Charles D.
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T cells ,ANTIGENS ,IMMUNE response ,IMMUNOGLOBULINS ,IMMUNOTHERAPY - Abstract
T cells proliferate vigorously following acute depletion of CD4+ Foxp3+ T regulatory cells [natural Tregs (nTregs)] and also when naive T cells are transferred to syngeneic, nTreg-deficient Rag1-/- hosts. Here, using mice raised in an antigen-free (AF) environment, we show that proliferation in these two situations is directed to self ligands rather than food or commensal antigens. In both situations, the absence of nTregs elevates B7 expression on host dendritic cells (DCs) and enables a small subset of naive CD4 T cells with high self affinity to respond overtly to host DCs: bidirectional T/DC interaction ensues, leading to progressive DC activation and reciprocal strong proliferation of T cells accompanied by peripheral Treg (pTreg) formation. Likewise, high-affinity CD4 T cells proliferate vigorously and form pTregs when cultured with autologous DCs in vitro in the absence of nTregs: this anti-self response is MHCII/peptide dependent and elicited by the raised level of B7 on cultured DCs. The data support a model in which self tolerance is imposed via modulation of CD28 signaling and explains the pathological effects of superagonistic CD28 antibodies. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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10. Regional Distribution of CNS Antigens Differentially Determines T-Cell Mediated Neuroinflammation in a CX3CR1-Dependent Manner.
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Rayasam, Aditya, Kijak, Julie A., Dallmann, McKenna, Hsu, Martin, Zindl, Nicole, Lindstedt, Anders, Steinmetz, Leah, Harding, Jeffrey S., Harris, Melissa G., Karman, Jozsef, Sandxor, Matyas, and Fabry, Zsuzsanna
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T cells ,AUTOIMMUNITY ,ANTIGENS ,ENCEPHALOMYELITIS ,IMMUNOGLOBULINS - Abstract
T cells continuously sample CNS-derived antigens in the periphery, yet it is unknown how they sample and respond to CNS antigens derived from distinct brain areas. We expressed ovalbumin (OVA) neoepitopes in regionally distinct CNS areas (Cnp-OVA and Nes-OVA mice) to test peripheral antigen sampling by OVA-specific T cells under homeostatic and neuroinflammatory conditions. We show that antigen sampling in the periphery is independent of regional origin of CNS antigens in both male and female mice. However, experimental autoimmune encephalomyelitis (EAE) is differentially influenced in Cnp-OVA and Nes-OVA female mice. Although there is the same frequency of CD45
high CD11b+ CD11c+ CX3CL1+ myeloid cell-T-cell clusters in neoepitope-expressing areas, EAE is inhibited in Nes-OVA female mice and accelerated in CNP-OVA female mice. Accumulation of OVA-specific T cells and their immunomodulatory effects on EAE are CX3C chemokine receptor 1 (CX3CR1) dependent. These data show that despite similar levels of peripheral antigen sampling, CNS antigen-specific T cells differentially influence neuroinflammatory disease depending on the location of cognate antigens and the presence of CX3CL1/CX3CR1 signaling. [ABSTRACT FROM AUTHOR]- Published
- 2018
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11. Quantitative analysis of the CD4+ T cell response to therapeutic antibodies in healthy donors using a novel T cell:PBMC assay.
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Schultz, Heidi S., Reedtz-Runge, Stine Louise, Bäckström, B. Thomas, Lamberth, Kasper, Pedersen, Christian R., Kvarnhammar, Anne M., and null, null
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T cells ,CD4 antigen ,ORGAN donors ,IMMUNOGLOBULINS ,BIOLOGICAL assay ,CYTOMEGALOVIRUSES ,PHYSIOLOGY - Abstract
Many biopharmaceuticals (BPs) are known to be immunogenic in the clinic, which can result in modified pharmacokinetics, reduced efficacy, allergic reactions and anaphylaxis. During recent years, several technologies to predict immunogenicity have been introduced, but the predictive value is still considered low. Thus, there is an unmet medical need for optimization of such technologies. The generation of T cell dependent high affinity anti-drug antibodies plays a key role in clinical immunogenicity. This study aimed at developing and evaluating a novel in vitro T cell:PBMC assay for prediction of the immunogenicity potential of BPs. To this end, we assessed the ability of infliximab (anti-TNF-α), rituximab (anti-CD20), adalimumab (anti-TNF-α) and natalizumab (anti-α4-integrin), all showing immunogenicity in the clinic, to induce a CD4
+ T cells response. Keyhole limpet hemocyanin (KLH) and cytomegalovirus pp65 protein (CMV) were included as neo-antigen and recall antigen positive controls, respectively. By analyzing 26 healthy donors having HLA-DRB1 alleles matching the European population, we calculated the frequency of responding donors, the magnitude of the response, and the frequency of BP-specific T cells, as measured by3 [H]-thymidine incorporation and ELISpot IL-2 secretion. KLH and CMV demonstrated a strong T cell response in all the donors analyzed. The frequency of responding donors to the BPs was 4% for infliximab, 8% for adalimumab, 19% for rituximab and 27% for natalizumab, which is compared to and discussed with their respective observed clinical immunogenicity. This study further complements predictive immunogenicity testing by quantifying the in vitro CD4+ T cell responses to different BPs. Even though the data generated using this modified method does not directly translate to the clinical situation, a high sensitivity and immunogenic potential of most BPs is demonstrated. [ABSTRACT FROM AUTHOR]- Published
- 2017
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12. B-CD8+ T Cell Interactions in the Anti-Idiotypic Response against a Self-Antibody.
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Martínez, Darel, Pupo, Amaury, Cabrera, Lianet, Raymond, Judith, Holodick, Nichol E., Hernández, Ana María, Martínez, Darel, and Hernández, Ana María
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GERM cells ,LABORATORY mice ,GANGLIOSIDES ,B cells ,T cells ,ANIMAL experimentation ,ANTIGENS ,AUTOANTIBODIES ,CELL communication ,IMMUNITY ,IMMUNIZATION ,IMMUNOGLOBULINS ,IMMUNOLOGICAL tolerance ,IMMUNOLOGY technique ,INTERFERONS ,INTERLEUKINS ,MICE ,MONOCLONAL antibodies - Abstract
P3 is a murine, germline, IgM mAb that recognizes N-glycolylated gangliosides and other self-antigens. This antibody is able to induce an anti-idiotypic IgG response and B-T idiotypic cascade, even in the absence of any adjuvant or carrier protein. P3 mAb immunization induces the expression of activation markers in a significant percentage of B-1a cells in vivo. Interestingly, transfer of both B-1a and B-2 to BALB/Xid mice was required to recover anti-P3 IgG response in this model. In fact, P3 mAb activated B-2 cells, in vitro, inducing secretion of IFN-γ and IL-4, although this activation was not detected ex vivo. Interestingly, naïve CD8+ T cells increased the expression of activation markers and IFN-γ secretion in the presence of B-1a cells isolated from P3 mAb-immunized mice, even without in vitro restimulation. In contrast, B-2 cells were able to stimulate CD8+ T cells only if P3 was added in vitro. Using bioinformatics, a MHC class I-binding peptide from P3 VH region was identified. P3 mAb was able to induce a specific CTL response in vivo against cells presenting this peptide. Both humoral and CTL anti-idiotypic responses could be mechanisms to protect against the self-reactive antibody, contributing to keeping the tolerance to self-antigens. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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13. Optimal Sequential Immunization Can Focus Antibody Responses against Diversity Loss and Distraction.
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Wang, Shenshen
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IMMUNOGLOBULINS ,IMMUNOLOGIC memory ,ANTIGENS ,VACCINATION ,LYMPHOCYTES - Abstract
Affinity maturation is a Darwinian process in which B lymphocytes evolve potent antibodies to encountered antigens and generate immune memory. Highly mutable complex pathogens present an immense antigenic diversity that continues to challenge natural immunity and vaccine design. Induction of broadly neutralizing antibodies (bnAbs) against this diversity by vaccination likely requires multiple exposures to distinct but related antigen variants, and yet how affinity maturation advances under such complex stimulation remains poorly understood. To fill the gap, we present an in silico model of affinity maturation to examine two realistic new aspects pertinent to vaccine development: loss in B cell diversity across successive immunization periods against different variants, and the presence of distracting epitopes that entropically disfavor the evolution of bnAbs. We find these new factors, which introduce additional selection pressures and constraints, significantly influence antibody breadth development, in a way that depends crucially on the temporal pattern of immunization (or selection forces). Curiously, a less diverse B cell seed may even favor the expansion and dominance of cross-reactive clones, but only when conflicting selection forces are presented in series rather than in a mixture. Moreover, the level of frustration due to evolutionary conflict dictates the degree of distraction. We further describe how antigenic histories select evolutionary paths of B cell lineages and determine the predominant mode of antibody responses. Sequential immunization with mutationally distant variants is shown to robustly induce bnAbs that focus on conserved elements of the target epitope, by thwarting strain-specific and distracted lineages. An optimal range of antigen dose underlies a fine balance between efficient adaptation and persistent reaction. These findings provide mechanistic guides to aid in design of vaccine strategies against fast mutating pathogens. [ABSTRACT FROM AUTHOR]
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- 2017
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14. Preparation and characterization of a novel nanobody against T-cell immunoglobulin and mucin-3 (TIM-3).
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Homayouni, Vida, Ganjalikhani-hakemi, Mazdak, Rezaei, Abbas, Khanahmad, Hossein, Behdani, Mahdi, and Lomedasht, Fatemeh Kazemi
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T cells ,IMMUNOGLOBULINS ,MUCINS ,IMMUNE response ,ANTIGENS ,PROTEIN expression ,NITRILOTRIACETIC acid - Abstract
Objective(s): As T cell immunoglobulin and mucin domain 3 (TIM 3) is an immune regulatory molecule its blocking or stimulating could alter the pattern of immune response towards a desired condition. Based on the unique features of nanobodies, we aimed to construct an anti TIM 3 nanobody as an appropriate tool for manipulating immune responses for future therapeutic purposes. Materials and Methods: We immunized a camel with TIM 3 antigen and then, synthesized a VHH phagemid library from its B cell s transcriptome using nested PCR. Library selection against TIM 3antigen was performed in three rounds of panning. Using phage ELISA, the most reactive colonies were selected for sub cloning in soluble protein expression vectors. The Nanobody was purified and confirmed with a nickel-nitrilotriacetic acid (Ni NTA) column, SDS PAGE and Western blotting. A flowcytometric analysis was performed to analyze the binding and biologic activities of theTIM 3 specific nanobody with TIM 3 expressing HL 60 and HEK cell lines. Results: Specific 15kD band representing for nanobody was observed on the gel and confirmed with Western blotting. The nanobody showed significant specific immune reactivity against TIM 3 with a relatively high binding affinity. The nanobody significantly suppressed the proliferation of TIM 3 expressing HL 60 cell line. Conclusion: Finally, we successfully prepared a functional anti humanTIM 3 specific nanobody with a high affinity and an anti-proliferative activity on an AML cell line in vitro. [ABSTRACT FROM AUTHOR]
- Published
- 2016
15. The Role of TLR4 on B Cell Activation and Anti-2GPI Antibody Production in the Antiphospholipid Syndrome.
- Author
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Cheng, Si, Wang, Haibo, and Zhou, Hong
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TOLL-like receptors , *B cells , *ANTIPHOSPHOLIPID syndrome , *GLUCOSE 6-phosphatase , *IMMUNOGLOBULINS , *PATIENTS , *ANTIPHOSPHOLIPID syndrome treatment , *ANTIGENS , *AUTOANTIBODIES , *CELL differentiation , *CELL receptors , *CELLULAR signal transduction , *DRUG therapy , *CYTOKINES , *GLYCOPROTEINS , *IMMUNITY , *IMMUNOLOGY technique , *IMMUNOTHERAPY , *T cells , *TUMOR necrosis factors , *ANTIBODY formation - Abstract
High titer of anti-β2-glycoprotein I antibodies (anti-β2GPI Ab) plays a pathogenic role in antiphospholipid syndrome (APS). Numerous studies have focused on the pathological mechanism in APS; however, little attention is paid to the immune mechanism of production of anti-β2GPI antibodies in APS. Our previous study demonstrated that Toll-like receptor 4 (TLR4) plays a vital role in the maturation of bone marrow-derived dendritic cells (BMDCs) from the mice immunized with human β2-glycoprotein I (β2GPI). TLR4 is required for the activation of B cells and the production of autoantibody in mice treated with β2GPI. However, TLR4 provides a third signal for B cell activation and then promotes B cells better receiving signals from both B cell antigen receptor (BCR) and CD40, thus promoting B cell activation, surface molecules expression, anti-β2GPI Ab production, and cytokines secretion and making B cell functioning like an antigen presenting cell (APC). At the same time, TLR4 also promotes B cells producing antibodies by upregulating the expression of B-cell activating factor (BAFF). In this paper, we aim to review the functions of TLR4 in B cell immune response and antibody production in autoimmune disease APS and try to find a new way for the prevention and treatment of APS. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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16. Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge.
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Magini, Diletta, Giovani, Cinzia, Mangiavacchi, Simona, Maccari, Silvia, Cecchi, Raffaella, Ulmer, Jeffrey B., De Gregorio, Ennio, Geall, Andrew J., Brazzoli, Michela, and Bertholet, Sylvie
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MESSENGER RNA ,INFLUENZA vaccines ,GENE expression ,IMMUNOGLOBULINS ,NUCLEOPROTEINS - Abstract
Current hemagglutinin (HA)-based seasonal influenza vaccines induce vaccine strain-specific neutralizing antibodies that usually fail to provide protection against mismatched circulating viruses. Inclusion in the vaccine of highly conserved internal proteins such as the nucleoprotein (NP) and the matrix protein 1 (M1) was shown previously to increase vaccine efficacy by eliciting cross-reactive T-cells. However, appropriate delivery systems are required for efficient priming of T-cell responses. In this study, we demonstrated that administration of novel self-amplifying mRNA (SAM
® ) vectors expressing influenza NP (SAM(NP)), M1 (SAM(M1)), and NP and M1 (SAM(M1-NP)) delivered with lipid nanoparticles (LNP) induced robust polyfunctional CD4 T helper 1 cells, while NP-containing SAM also induced cytotoxic CD8 T cells. Robust expansions of central memory (TCM ) and effector memory (TEM ) CD4 and CD8 T cells were also measured. An enhanced recruitment of NP-specific cytotoxic CD8 T cells was observed in the lungs of SAM(NP)-immunized mice after influenza infection that paralleled with reduced lung viral titers and pathology, and increased survival after homologous and heterosubtypic influenza challenge. Finally, we demonstrated for the first time that the co-administration of RNA (SAM(M1-NP)) and protein (monovalent inactivated influenza vaccine (MIIV)) was feasible, induced simultaneously NP-, M1- and HA-specific T cells and HA-specific neutralizing antibodies, and enhanced MIIV efficacy against a heterologous challenge. In conclusion, systemic administration of SAM vectors expressing conserved internal influenza antigens induced protective immune responses in mice, supporting the SAM® platform as another promising strategy for the development of broad-spectrum universal influenza vaccines. [ABSTRACT FROM AUTHOR]- Published
- 2016
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17. Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics.
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Joubert, Marisa K., Deshpande, Meghana, Yang, Jane, Reynolds, Helen, Bryson, Christine, Fogg, Mark, Baker, Matthew P., Herskovitz, Jonathan, Goletz, Theresa J., Zhou, Lei, Moxness, Michael, Flynn, Gregory C., Narhi, Linda O., and Jawa, Vibha
- Subjects
BIOTHERAPY ,IMMUNOGLOBULINS ,MONONUCLEAR leukocytes ,T cells ,CELL proliferation - Abstract
An In Vitro Comparative Immunogenicity Assessment (IVCIA) assay was evaluated as a tool for predicting the potential relative immunogenicity of biotherapeutic attributes. Peripheral blood mononuclear cells from up to 50 healthy naïve human donors were monitored up to 8 days for T-cell proliferation, the number of IL-2 or IFN-γ secreting cells, and the concentration of a panel of secreted cytokines. The response in the assay to 10 monoclonal antibodies was found to be in agreement with the clinical immunogenicity, suggesting that the assay might be applied to immunogenicity risk assessment of antibody biotherapeutic attributes. However, the response in the assay is a measure of T-cell functional activity and the alignment with clinical immunogenicity depends on several other factors. The assay was sensitive to sequence variants and could differentiate single point mutations of the same biotherapeutic. Nine mAbs that were highly aggregated by stirring induced a higher response in the assay than the original mAbs before stirring stress, in a manner that did not match the relative T-cell response of the original mAbs. In contrast, mAbs that were glycated by different sugars (galactose, glucose, and mannose) showed little to no increase in response in the assay above the response to the original mAbs before glycation treatment. The assay was also used successfully to assess similarity between multiple lots of the same mAb, both from the same manufacturer and from different manufacturers (biosimilars). A strategy for using the IVCIA assay for immunogenicity risk assessment during the entire lifespan development of biopharmaceuticals is proposed. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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18. Comparative Immunogenicity of HIV-1 gp140 Vaccine Delivered by Parenteral, and Mucosal Routes in Female Volunteers; MUCOVAC2, A Randomized Two Centre Study.
- Author
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Cosgrove, Catherine A., Lacey, Charles J., Cope, Alethea V., Bartolf, Angela, Morris, Georgina, Yan, Celine, Baden, Susan, Cole, Tom, Carter, Darrick, Brodnicki, Elizabeth, Shen, Xiaoying, Joseph, Sarah, DeRosa, Stephen C., Peng, Lili, Yu, Xuesong, Ferrari, Guido, Seaman, Mike, Montefiori, David C., Frahm, Nicole, and Tomaras, Georgia D.
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MUCOUS membranes ,IMMUNIZATION ,IMMUNOGLOBULINS ,HEPATITIS C virus ,INTRAMUSCULAR injections - Abstract
Background: Defining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses. Methods: In this randomized two center phase I clinical trial we evaluated the systemic and mucosal immune response to a candidate HIV-1 Clade C CN54gp140 envelope glycoprotein vaccine administered by intramuscular (IM), intranasal (IN) and intravaginal (IVAG) routes of administration in HIV negative female volunteers. IM immunizations were co-administered with Glucopyranosyl Lipid Adjuvant (GLA), IN immunizations with 0.5% chitosan and IVAG immunizations were administered in an aqueous gel. Results: Three IM immunizations of CN54 gp140 at either 20 or 100 μg elicited significantly greater systemic and mucosal antibodies than either IN or IVAG immunizations. Following additional intramuscular boosting we observed an anamnestic antibody response in nasally primed subjects. Modest neutralizing responses were detected against closely matched tier 1 clade C virus in the IM groups. Interestingly, the strongest CD4 T-cell responses were detected after IN and not IM immunization. Conclusions: These data show that parenteral immunization elicits systemic and mucosal antibodies in women. Interestingly IN immunization was an effective prime for IM boost, while IVAG administration had no detectable impact on systemic or mucosal responses despite IM priming. Clinical Trials Registration: EudraCT 2010-019103-27 and the UK Clinical Research Network (UKCRN) Number 11679 [ABSTRACT FROM AUTHOR]
- Published
- 2016
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19. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPAR α and T- and B-cell targeting.
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DeWitt, Jamie C., Williams, Wanda C., Creech, N. Jonathan, and Luebke, Robert W.
- Subjects
B cells ,T cells ,PERFLUOROOCTANOIC acid ,ANTIGENS ,IMMUNOGLOBULINS ,LABORATORY mice ,PEROXISOME proliferator-activated receptors - Abstract
T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARα)-dependent and if suppression is associated with specific targeting of T- or B-cells, three separate experiments were conducted: (1) female PPARαconstitutive knockout (PPARαKO; B6.129S4-Ppartm1GonzN12) and wild-type controls (WT; C57BL/6-Tac) exposed to 0, 7.5, or 30 mg PFOA/kg for 15 days were immunized on Day 11 with a T-cell-dependent antigen and sera then collected for measures of antigen-specific IgM titers (TDAR) 5 days later; (2) female C57BL/6N WT mice exposed to 0, 0.94, 1.88, 3.75, or 7.5 mg PFOA/kg for 15 days were immunized with a T-cell-independent antigen on Day 11 and sera were then collected for analyses of antigen-specific IgM titers (TIAR) 7 days later; and (3) splenic lymphocyte phenotypes were assessed in unimmunized female C57BL/6N WT mice exposed to 0, 3.75, or 7.5 mg PFOA/kg for 10 days to investigate effects of PFOA in the absence of specific immunization. Separate groups of mice were immunized with a T-cell-dependent antigen after 11 days of exposure and splenic lymphocyte sub-populations were assessed after 13 or 15 days of exposure to assess numbers of stimulated cells. The results indicated that exposure to ≥1.88 mg PFOA/kg suppressed the TIAR; exposure to 30 mg PFOA/kg suppressed the TDAR in both PPARαKO and WT mice. The percentage of splenic B-cells was unchanged. Results obtained in the PPARαKO mice indicated that PPARαsuppression of TDAR was independent of PPARαinvolvement. Suppression of the TIAR and the TDAR with minimal lymphocyte sub-population effects suggested that effects on humoral immunity are likely mediated by disruption of B-cell/plasma cell function. [ABSTRACT FROM PUBLISHER]
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- 2016
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20. Induction of HLA-B*40:02-restricted T cells possessing cytotoxic and suppressive functions against haematopoietic progenitor cells from a patient with severe aplastic anaemia.
- Author
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Inaguma, Yoko, Akatsuka, Yoshiki, Hosokawa, Kohei, Maruyama, Hiroyuki, Okamoto, Akinao, Katagiri, Takamasa, Shiraishi, Keiko, Murayama, Yuko, Tsuzuki‐Iba, Sachiko, Mizutani, Yuuki, Nishii, Chikako, Yamamoto, Naoki, Demachi‐Okamura, Ayako, Kuzushima, Kiyotaka, Ogawa, Seishi, Emi, Nobuhiko, and Nakao, Shinji
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ANEMIA treatment ,HUMAN leucocytes ,ANTIGENS ,IMMUNOGLOBULINS ,T cells ,PROGENITOR cells - Abstract
The article offers information on a study concerning induction of human leucocyte antigen (HLA)-B restricted T cells possessing cytotoxic and suppressive functions against haematopoietic progenitor cells from a patient with severe aplastic anaemia. Topics discussed include treatment of acquired aplastic anaemia (AA) with antithymocyte globulin and ciclosporin (CsA), bone marrow (BM) hypoplasia and pancytopenia, and immune pressure of autoreactive cytotoxic T lymphocytes.
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- 2016
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21. Immunoglobulin and CD8+ T-cell distribution in histologically distinctive tonsils of individuals with tonsillar focal infection.
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Meng, Hong-xue, Ohe, Rintaro, Li, Hui-ning, Yang, Su-ran, Kabasawa, Takanobu, Kato, Tomoya, Zhang, Lei, Ohtake, Hiroya, Ishida, Akihiro, Ohta, Nobuo, Jin, Xiao-ming, Kakehata, Seiji, and Yamakawa, Mitsunori
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ACADEMIC medical centers ,ANTIGENS ,AUTOIMMUNE diseases ,CYTOKINES ,GLOMERULONEPHRITIS ,IMMUNOGLOBULINS ,IMMUNOHISTOCHEMISTRY ,RESEARCH methodology ,POLYMERASE chain reaction ,PSORIASIS ,RESEARCH funding ,RHEUMATOID arthritis ,T cells ,T-test (Statistics) ,TISSUE culture ,TONSILLITIS ,REVERSE transcriptase polymerase chain reaction ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Conclusion: This study demonstrated that the common immunological mechanism, which involves aberration of immunoglobulin and T-cell distribution in histologically distinctive tonsils, may be associated with the pathogenesis of tonsillar focal infection. Objectives: Tonsillar focal infection comprises a group of relatively common diseases combined with chronic tonsillar infection, is associated with unusual immune responses in tonsils, and may cause lesions in another distant target organ. This study aimed to investigate the distribution of inflammatory T cells and T-cell regulatory elements, such as programmed cell death-1 (PD-1) and Fork head box protein 3 (Foxp3), immunoglobulin production, and histological characteristics in tonsils from patients with tonsillar focal infection. Methods: Immunohistochemistry and reverse transcription-polymerase chain reaction (PCR) were used to compare the expression of CD8
+ T cells, immunoglobulins, and cytokines associated with immunoglobulin production in the tonsils of patients with IgA nephropathy (IgAN), palmoplantar pustulosis (PPP), rheumatoid arthritis (RA), and chronic tonsillitis. Results: The overexpression of CD8+ T cells combined with decreased expression of Foxp3 and PD-1 and the aberration of immunoglobulin production, which may be due to the elevated expression of activation-induced deaminase (AID), B-cell-activating factor of the TNF family (BAFF), supporting isotype switching, and B-cell survival in the histologically distinctive tonsils. [ABSTRACT FROM AUTHOR]- Published
- 2015
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22. Sulphite oxidase (SO) - a mitochondrial autoantigen as target for humoral and cellular immune reactions in primary sclerosing cholangitis.
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Preuß, Beate E., Berg, Christoph P., Werner, Christoph, Plankenhorn, Sandra, Malek, Nisar P., and Klein, Reinhild
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OXIDATION of sulfites ,CHOLANGITIS ,URSODEOXYCHOLIC acid ,IMMUNOGLOBULIN G ,IMMUNE response ,AUTOANTIGENS ,B cells ,T cells ,GASTROINTESTINAL agents ,ANTIGENS ,AUTOANTIBODIES ,BILE duct diseases ,CELLULAR immunity ,GENE expression ,IMMUNOGLOBULINS ,IMMUNOLOGY technique ,MITOCHONDRIA ,OXIDOREDUCTASES ,ANTIBODY formation ,THERAPEUTICS ,PHYSIOLOGY - Abstract
Background: In a recent study we had evidence that sulphite oxidase (SO) may be a relevant autoantigen in primary sclerosing cholangitis (PSC). Aim of the present study was, therefore, to analyse humoral and cellular immune-reactivity towards SO in these patients in more detail.Methods: Sera from 53 patients with PSC (30 untreated and 23 treated with ursodeoxycholic acid [UDCA] at time of analysis), from 422 patients with different hepatic and non-hepatic disorders, and from 50 healthy individuals were tested by ELISA for antibodies against full-length-SO (SO-fl) and its three major domains expressed in E.coli (SO-I, SO-II, SO-III). For epitope-mapping, 29 overlapping peptides were used. Peripheral blood mononuclear cells (PBMC) were obtained from 33 PSC-patients and analysed for SO-induced proliferation, production of cytokines, and expression of the activation marker cluster of differentiation (CD) 69.Results: 43% of the 30 untreated and 26% of the 23 treated PSC-patients had IgG anti-SO-antibodies predominantly reacting with SO-fl, SO-I and SO-II. Antibody-reactivity decreased after UDCA-treatment. Prevalence and reactivity of anti-SO-antibodies were significantly higher in PSC than in patients with other hepatic and non-hepatic disorders. Epitope mapping revealed no distinct immuno-dominant regions within SO. Incubation of PBMC from PSC-patients (but not from controls) with SO-antigens revealed an activation of B-cells and a T-helper cell type-2 reaction pattern (production of interleukin [IL]-13, IL-10).Conclusions: PSC-patients show humoral and cellular immune response towards SO. Antibodies may be predominantly directed against conformational epitopes. SO enhances in vitro especially T-helper cell type-2 immune-reactions, which may be pro-fibrotic. SO is a detoxifying enzyme present also in bacteria; further studies analysing its role in the aetiology and pathogenesis in PSC may, therefore, be important. [ABSTRACT FROM AUTHOR]- Published
- 2018
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23. Checkpoint Inhibitors and Other Immune Therapies for Hodgkin and Non-Hodgkin Lymphoma.
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Matsuki, Eri and Younes, Anas
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ANTINEOPLASTIC agents ,THERAPEUTIC use of immunoglobulins ,IMMUNOLOGICAL adjuvants ,THERAPEUTIC use of monoclonal antibodies ,ANTIGENS ,DRUG therapy ,CLINICAL trials ,HODGKIN'S disease ,IMMUNOGLOBULINS ,IMMUNOTHERAPY ,LYMPHOMAS ,MONOCLONAL antibodies ,RESEARCH funding ,T cells ,TREATMENT effectiveness ,THERAPEUTICS - Abstract
Opinion Statement: Treatment for relapsed/refractory (R/R) Hodgkin and non-Hodgkin lymphoma remains challenging. The introduction of rituximab to B cell non-Hodgkin lymphoma (B-NHL) treatment significantly improved patients' response rate and survival; however, approximately one third of patients with diffuse large B cell lymphoma, the most common B-NHL subtype, still have a relapse or become refractory after first-line therapy. More recently, antibody therapies and small-molecule inhibitors were approved for treating R/R lymphomas; these agents include brentuximab vedotin, ibrutinib, and idelalisib. Immune checkpoint inhibitors and other immune therapies are emerging treatments currently being evaluated in various clinical trials for their efficacy against lymphoid malignancies. Striking results from these treatment modalities have been observed in solid tumors, and evidence is accumulating to support their use in various lymphomas. The most exciting results from immune checkpoint inhibitor therapy have been seen in patients with R/R Hodgkin lymphoma, in whom the overall response rate has reached 60-80 %. Results in NHL are more similar to those seen in other solid malignancies, ranging between 20 and 40 %, depending on the histology. Formal approval of these drugs is being awaited, as are the results of combination therapy with checkpoint inhibitors and other treatment modalities, including conventional chemotherapy, small-molecule inhibitors, and other immune therapies. Although response rates have been promising, attention must be paid to the management of unique immune-related adverse events, which warrant close monitoring in some cases. Identification of biomarkers that predict response or severe adverse events using either the tumor specimen or peripheral blood would aid in selecting patients suited for these types of treatment as well as determining the ideal sequence of treatment within the realm of immune therapies. [ABSTRACT FROM AUTHOR]- Published
- 2016
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