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In this paper, we consider the combined effects of cytotoxic T lymphocyte (CTL) responses on the competition dynamics of two Simian immunodeficiency virus (SIV) strains model. One of strains concerns a relatively slowly replicating and mildly cytopathic virus in the early infection (SIVMneCL8), the other is faster replicating and more cytopathic virus at later stages of the infection (SIVMne170). It is shown that the global dynamics of the ordinary differential equations can be determined by several threshold parameters, and we prove the global stability of the equilibria by rigorous mathematical analysis. To account for a series of infection mechanism leading to viral production, we incorporate time delays in the infection term. Using the methods of constructing suitable Lyapunov functionals and LaSalle’s invariance principle, we obtain the sufficient conditions for the global attractiveness of infection-free equilibrium with both virus strains going extinct, single-infection equilibrium with one of two virus strains out-competing the other one and the two strains coexisting infection equilibrium. We establish that the intracellular delays can destabilize the single-infection equilibrium leading to Hopf bifurcation and periodic oscillations. We show that introduction of immune responses is responsible for the coexistence of two virus strains and the intracellular delays may alter the two-strain competition results. Numerical simulations are presented to illustrate the theoretical conclusions. [ABSTRACT FROM AUTHOR]

Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70), a member of Syk family (non-receptor protein tyrosine kinase family), has an imperative function in the immune cell signaling in T cells. Its role in T-cell development has been established by the severe combined immune deficiency syndrome in ZAP-70 deficient humans. Moreover, defects in T-cell activation and downstream signaling events were observed in T-cells that lack ZAP-70. Thus, the crucial role of ZAP-70 in the development and activation of T-cell and its predominant expression in T-cells make it a logical target for the treatment of pathological conditions related to abnormal T-cell responses. The present review article portrays the domain structure of ZAP-70 along with its implication in T-cell signaling. Additionally, varied ZAP-70 inhibitors published in different patents and papers have also been reviewed. [ABSTRACT FROM AUTHOR]

The mass action infection law, the most frequently used transmission process in the theoretical studies of disease dynamics, has been challenged in various ways. Hill type infection rate is supposed to be a better alternative to mass action law. In the first phase of this paper, we study a basic HIV model with Hill type infection rate. In the second phase, we modify our basic model with intracellular delay τ that measures the time between the first effective contact between a virus and a healthy CD4 + T cell and the latter becomes productively infective. Mathematical results like well-posedness, permanence, local stability and global stability of both the delayed and non-delayed systems are studied. It is observed that the endemic equilibrium is locally and globally asymptotically stable if the virus replication factor is greater than a threshold value and unstable otherwise. In the latter case, the disease-free steady state occurs and is proved to be globally asymptotically stable. Our simulation results shed different insights on drug therapy when various perturbations are given to the system. It is shown that multi-blockers drug therapy is more appropriate in the treatment of HIV patients in comparison to any mono-blocker drug therapy. [ABSTRACT FROM AUTHOR]

Establishment and maintenance of pregnancy represents a challenge for the maternal immune system since it has to defend against pathogens and tolerate paternal alloantigens expressed in fetal tissues. Regulatory T (Treg) cells, a subset of suppressor CD4 + T cells, play a dominant role in the maintenance of immunological self-tolerance by preventing immune and autoimmune responses against self-antigens. Although localized mechanisms contribute to fetal evasion from immune attack, in the last few years it has been observed that Treg cells are essential in promoting fetal survival avoiding the recognition of paternal semi-allogeneic tissues by maternal immune system. Several functional studies have shown that unexplained infertility, miscarriage and pre-clampsia are often associated with deficit in Treg cell number and function while normal pregnancy selectively stimulates the accumulation of maternal forkhead-box-P3 + (FoxP3 + ) CD4 + Treg cells with fetal specificity. Some papers have been reported that the number of Treg cells persists at elevated levels long after delivery developing an immune regulatory memory against father's antigens, moreover these memory Treg cells rapidly proliferate during subsequent pregnancies, however, on the other hand, there are several evidence suggesting a clear decline of Treg cells number after delivery. Different factors such as cytokines, adipokines, pregnancy hormones and seminal fluid have immunoregulatory activity and influence the success of pregnancy by increasing Treg cell number and activity. The development of strategies capable of modulating immune responses toward fetal antigens through Treg cell manipulation, could have an impact on the induction of tolerance against fetal antigens during immune-mediated recurrent abortion. [ABSTRACT FROM AUTHOR]

In previous reports, we had shown in Camelus dromedarius that diversity in T cell receptor gamma (TRG) and delta (TRD) variable domains can be generated by somatic hypermutation (SHM). In the present paper, we further the previous finding by analyzing 85 unique spleen cDNA sequences encoding a total of 331 mutations from a single animal, and comparing the properties of the mutation profiles of dromedary TRG and TRD variable domains. The transition preference and the significant mutation frequency in the AID motifs (dgyw/wrch and wa/tw) demonstrate a strong dependence of the enzymes mediating SHM in TRG and TRD genes of dromedary similar to that of immunoglobulin genes in mammals. Overall, results reveal no asymmetry in the motifs targeting, i.e. mutations are equally distributed among g:c and a:t base pairs and replacement mutations are favored at the AID motifs, whereas neutral mutations appear to be more prone to accumulate in bases outside of the motifs. A detailed analysis of clonal lineages in TRG and TRD cDNA sequences also suggests that clonal expansion of mutated productive rearrangements may be crucial in shaping the somatic diversification in the dromedary. This is confirmed by the fact that our structural models, computed by adopting a comparative procedure, are consistent with the possibility that, irrespective of where (in the CDR-IMGT or in FR-IMGT) the diversity was generated by mutations, both clonal expansion and selection seem to be strictly related to an enhanced structural stability of the γδ subunits. [ABSTRACT FROM AUTHOR]

CD2BP2 (CD2 cytoplasmic tail binding protein 2), one of several proteins interacting with the cytoplasmic tail of CD2, plays a crucial role in CD2-triggered T cell activation and nuclear splicing. The studies on CD2BP2 have tended to be confined to a few mammals, and little information is available to date regarding fish CD2BP2. In this paper, a CD2BP2 gene (On-CD2BP2) was cloned from Nile tilapia, Oreochromis niloticus. Sequence analysis showed that the full length of On-CD2BP2 cDNA was 1429 bp, containing a 5'untranslated region (UTR) of 111 bp, a 3'-UTR of 193 bp and an open reading frame of 1125 bp which is encoding 374 amino acids. Two important structural features, a GYF domain and a consensus motif GPFXXXXMXXWXXXGYF were detected in the deduced amino acid sequence of On-CD2BP2, and the deduced genomic structure of On-CD2BP2 was similar to the known CD2BP2. The mRNA expression of On-CD2BP2 in various tissues of Nile tilapia was analyzed by fluorescent quantitative real-time PCR. In healthy Nile tilapia, the On-CD2BP2 transcripts were mainly detected in the head kidney and spleen. While vaccinated with inactivated Streptococcus agalactiae, the On-CD2BP2 mRNA expression was significantly up-regulated in the head kidney, spleen and brain 48 h post immunization. Moreover, there was a clear time-dependent expression pattern of On-CD2BP2 after immunization and the expression reached the highest level at 24 h in the brain and 48 h in the head kidney and spleen. This is the first report of proving the presence of a CD2BP2 ortholog in fish, and investigating its tissue distribution and expression profile in response to bacterial stimulus. These findings indicated that On-CD2BP2 may play an important role in the immune response to bacteria in Nile tilapia. [ABSTRACT FROM AUTHOR]

Transforming growth factor-beta (TGF-β) is a cytokine with pleiotropic functions in hematopoiesis, angiogenesis, cell proliferation, differentiation, migration and apoptosis. Although its role in rheumatoid arthritis is not well defined, TGF-β activation leads to functional immunomodulatory effects according to environmental conditions. The function of TGF-β in the development of arthritis in murine models has been extensively studied with controversial results. Recent findings point to a non-relevant role for TGF-p in a mice model of collagen-induced arthritis. The study of TGF-β on T-cell responses has shown controversial results as an inhibitor or promoter of the inflammatory response. This paper presents a review of the role of TGF-β in animal models of arthritis. [ABSTRACT FROM AUTHOR]

Abstract: Oridonin is a natural compound purified from Rabdosia rubescens that has remarkable anti-inflammatory and antitumor activities. Although oridonin has been used in traditional Chinese medicine for many years to treat inflammatory diseases, the underlying mechanisms of these activities are not well understood. In this paper, we explored whether oridonin could be used in transplantation and the mechanisms of its immunosuppression. Oridonin efficacy in transplantation is manifested by prolonged graft survival and decreased graft infiltration. Oridonin induces T cell apoptosis in a concentration- and time-dependent manner. In vivo, oridonin depleted large numbers of T cells from the spleen and peripheral blood. Decreased T cell numbers resulted from apoptosis, which was accompanied by increased phagocyte numbers in the periphery. Reduction in the number of thymocytes was observed in mice treated for 8days, and CD4+CD8+ cells were more sensitive to apoptosis induced by oridonin. Additionally, successive treatment with oridonin for 16days resulted in a considerable reduction in the total number of spleen cells and spleen volume. Thus, T cell depletion may play an essential role in prolonged graft survival and immunosuppression induced by oridonin. [Copyright &y& Elsevier]

Abstract: Context: Benign prostatic hyperplasia (BPH) is one of the most common diseases associated with the aging process in men, particularly men aged >50 yr, yet only a few predictive factors have been identified. In recent years, attention has focused on the role of prostatic inflammation in the pathogenesis and progression of BPH. Objective: This article reviews recent findings related to the potential link between local and systemic inflammation and BPH. Evidence acquisition: In March 2013, at the annual meeting of the European Association of Urology in Milan, Italy, a satellite symposium entitled “Benign Prostatic Hypertrophy (BPH) and Inflammation, from Lab to Clinic,” was held with the goal of reviewing the latest data relating to the link between inflammation and BPH. This paper is based on one of the presentations at this symposium. A structured PubMed literature search was performed, and emphasis was placed on results from the past 10 yr. Evidence synthesis: BPH is characterized by progressive hyperplasia of stromal and glandular cells, and clinically it is defined by lower urinary tract symptoms. In recent years, there has been accumulating evidence linking prostatic inflammation with BPH. The inflammatory infiltrates observed in patients with BPH are composed primarily of chronically activated T-lymphocytes. Cytokines and growth factors released from inflammatory cells create a proinflammatory environment that may support the fibromuscular growth seen in BPH and may also be responsible for inducing a state of relative hypoxia as a result of the increased oxygen demand of the proliferating cells. A number of clinical studies have confirmed the presence of inflammatory infiltrate in men with BPH, and this infiltrate has been shown to be involved in the pathogenesis, clinical appearance, and progression of this disorder. There is evidence emerging that systemic inflammation may also play a role in BPH, since in men with metabolic syndrome there was a significant correlation between prostate diameter/volume and the number of metabolic syndrome components. Conclusions: It is clear that a number of different mechanisms are involved in the development and progression of BPH. Prostatic inflammation is an important feature, since it appears to be involved in the pathogenesis, symptomatology, and progression of the disease. [Copyright &y& Elsevier]

Abstract: NK cells are a major group of immune cells responsible for the phenomenon of natural, innate cytotoxicity. One of the better studied receptors of human NK cells are killer cell immunoglobulin-like receptors (KIR) responsible for checking the presence of MHC class I molecules, which serve as their ligands. Although previously treated as specific for NK cells, nowadays these receptors are known to also occur on T cells. Genetics of KIR molecules is very complicated, what create a great variability of haplotypes in various populations world-wide. In addition, some KIR are known to recognize HLA-C (epitopes C1 or C2), HLA-B (Bw4) or HLA-A (A3 and/or A11) molecules. Therefore, this makes a huge diversity of reactions among individuals, depending on the presence or absence of given KIR and their ligands, hence differential susceptibility to several diseases, including various dermatoses. This paper underlines the important role of both KIR genotypes and HLA class I genes with reference to the various skin diseases. [Copyright &y& Elsevier]

Abstract: Myasthenia gravis (MG) is an antibody mediated, T cell dependent autoimmune disease characterized by muscle fatigability in which autoantibodies directed to the acetylcholine receptor (AChR) impair neuromuscular transmission. The identification of CD4+CD25+Foxp3+ Treg cells as important regulators of tolerance opened a major area of investigation raising the possibility that a dysfunction in the Treg compartment is involved in the etiology and pathogenesis of autoimmune diseases, including MG. In this paper we summarize shortly Treg abnormalities that were reported in MG patients and report on our studies of Treg in experimental autoimmune MG (EAMG). Hopefully these studies would pave the way towards the development of novel Treg-based treatment modalities that will restore self-tolerance in MG and other autoimmune diseases. In our previous studies in EAMG we have shown that Treg cells transferred from healthy rat donors to myasthenic rats suppress EAMG. However, Treg cells from sick animals do not have the same in vivo suppressive activity as those from healthy donors. The objective of the present study was to further characterize quantitative and qualitative alterations in Treg cells of rats with EAMG. We found that the frequency of CD4+CD25+Foxp3+ Treg cells within the spleen and PBL was decreased in EAMG rats as compared to naïve and CFA-immunized healthy controls. Treg cells from myasthenic rats were less effective than Treg cells from controls in suppressing the proliferation of CD4+ T effector cells in response to ConA and of B cells in response to LPS. Moreover, CD4+CD25+ cells from EAMG rats exhibited an elevated extent of apoptosis and expressed upregulated levels of FAS and of Th17-associated cytokines. Since EAMG is an induced disease, these quantitative and qualitative alterations in Treg cells do not reflect predisposing impairments and seem to be associated with the specific autoimmune response resulting from AChR immunization. [Copyright &y& Elsevier]

The holy grail for HIV-1 vaccine researchers is to develop an efficacious vaccine, a goal that would be aided by defining a correlate of protection from infection. Recently, the authors of two papers have come one step closer to this goal with the definition of a correlate of survival following simian immunodeficiency virus (SIV) infection: the preservation of memory CD4+ T cells during acute infection. Both of these research groups show that vaccination can prevent the initial immune devastation caused by SIV infection and that this correlates with survival following SIV challenge. Here, we highlight the significance of these two recent papers in light of the urgent need to produce an efficacious HIV vaccine and discuss several crucial issues that must be addressed before the correlate can be used in human clinical trials. [Copyright &y& Elsevier]

The reason for low- or non-immunogenicity of fish collagens is still in doubt, which, to some extent, bottlenecks their production and clinical application as biomaterials. Employing bovine or porcine type I collagens (BCI or PCI) as controls in this paper, we intensively investigate the influence of tilapia type I collagens (TCI) on the function of dendritic cells (DCs) and T cells. From bio-informatic analyses, as well as data obtained in vitro and in vivo , we find the variations in amino acid sequences lead to only one calcium binding motif in the secondary structure of TCI, compared with three in BCI or PCI. So when TCI (together with the minor amount of Ca2+ they take) are uptaken, intracellular [Ca2+] remains stable and DCs maintain immature. On the contrary, those that have uptaken PCI or BCI experience not only increased [Ca2+] in the plasma but also phosphorylation of p65, resulting in activation of STIM1-Orai1/NF-кB signaling pathway and DC maturation. We fully prove our results on mice models, with no obvious cellular and humoral immune reactions. Our study primarily reveal the underlying mechanisms why TCI, different from BCI or PCI, show almost non-immunogenicity. Our findings are of great importance for the promotion and wide application of TCI in biomedicine. [Display omitted] • Tilapia type I collagens (TCI) do not induce DC maturation. • TCI do not enhance intracellular [Ca2+] by not activating STIM1-Orai1/NF-кB pathway. • Variations in amino acid sequences result in different numbers of calcium ligands. • TCI show lower immunogenicity than terrestrial mammals both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) play a pivotal role in initiating antigen-specific tumor immunity. However, the abnormal function of DCs owing to the immunosuppressive tumor microenvironment (TME) and the insufficient number of tumor infiltrating DCs could promote immune tolerance and tumor immune escape. Thus, there is great potential to employ DCs to induce efficient antitumor immunity. In this paper, we developed intelligent DCs (iDCs), which consist of nanoparticles loaded with photothermal agents (IR-797) and coated with a mature DC membrane. The DC cell membrane on the surface of iDCs preserves the ability to present antigens and prime T cells. The iDCs can also enter the lymph node and stimulate T cells. The activated T cells reduced the expression of heat shock proteins (HSPs) in tumor cells, rendering them more sensitive to heat stress. Subsequently, we used mild photothermal therapy (42–45 °C) to induce immunogenic cell death and contribute to a synergistic antitumor effect. iDCs as a refined and precise system in combination with DC-based immunotherapy and thermal therapy can be stored long-term and on a large scale, so they can be applied in many patients. [ABSTRACT FROM AUTHOR]

• Major immune effector cells like CD8+ T lymphocytes and natural killer cells are able to kill or inhibit Hepatocellular carcinoma (HCC) cells and their cytotoxic ability can be enhanced or down-regulated by certain cytokines or drugs. • HCC cells can impair the function of major immune effector cells through a variety of mechanisms. • Organoids or direct contact cell co-culture especially with primary HCC cells and tumor infiltrating lymphocytes provide better understanding of cell–cell interactions between major immune effector cells and HCC cells. • Immunotherapy like checkpoint inhibitors and adoptive cell transfer showed notable effectiveness and safety in preventing HCC recurrence as adjuvant therapy. Hepatocellular carcinoma (HCC) is the most common liver neoplasm with high morbidity and mortality. Tumor immunotherapy might be promising adjuvant therapy for HCC after surgery. To better develop HCC immunotherapy, comprehensive understanding of cell–cell interactions between immune effector cells and HCC cells remains crucial. To review the existing studies to summarize the cell–cell interactions between major immune effector cells and HCC cells providing new data for HCC immunotherapy. A systematic review was conducted by searching PubMed database covering all papers published in recent five years up to January 2020. The guidelines of the preferred reporting items for systematic reviews were firmly followed. There are 9 studies researching the interactions between CD8+ T lymphocytes and HCC cells and 22 studies researching that between natural killer (NK) cells and HCC cells. Among the 9 studies, 6 studies reported that CD8+ T lymphocytes showed cytotoxicity towards HCC cells while 3 studies found CD8+ T lymphocytes were impaired by HCC cells. Among the 22 studies, 20 studies presented that NK cells could inhibit HCC cells. Two studies were found to report NK cell dysfunction in HCC. Based on the systematic analysis, we concluded that CD8+ T lymphocytes and NK cells can inhibit HCC cells. While in turn, HCC cells can also result in the dysfunction of those effector cells through various mechanisms. Organoids and direct contact cell co-culture with primary HCC cells and TILs should be the most innovative way to investigate the interactions and develop novel immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: This paper investigates the in vitro effect of dexamethasone on bovine CD25highCD4+, CD25lowCD4+ and CD25−CD4+ T cells. Only a small percentage of bovine CD25highCD4+ (2–4%) and CD25lowCD4+ (1–2%) cells expressed Foxp3. Dexamethasone caused considerable loss of CD25−CD4+ cells, but it increased the relative and absolute numbers of CD25highCD4+ and CD25lowCD4+ lymphocytes, while at the same time reducing the percentage of Foxp3+ cells within the latter subpopulations. Considering all these, as well as the intrinsically poor Foxp3 expression in bovine CD25+CD4+, it can be concluded that the drug most probably increased the number of activated non-regulatory CD4+ lymphocytes. It has been found that changes in cell number were at least partly caused by proapoptotic effect of the drug on CD25−CD4+ cells and antiapoptotic effect on CD25highCD4+ and CD25lowCD4+ cells. The results obtained from this study indicate that the involvement of CD4+ lymphocytes in producing the anti-inflammatory and immunosuppressive effect of dexamethasone in cattle results from the fact that the drug had a depressive effect on the production of IFN-γ by CD25−CD4+ cells. Secretion of TGF-β and IL-10 by CD4+ lymphocytes was not involved in producing these pharmacological effects, because the drug did not affect production of TGF-β and, paradoxically, it reduced the percentage of IL-10+CD4+ cells. [Copyright &y& Elsevier]

Abstract: This paper describes an immune-inspired system based on an alternate theory about the self–nonself distinction theory, which defines the negative selection process as a mechanism of a fuzzy system based on the affinity between antigen and T-cells. This theory may provide a decision making tool which improves the generation of detectors or even define new data monitoring in order to detect an extreme variation of the system behavior, which means anomalies occurrences. Through these algorithms, tests are performed to detect faults of a DC motor. Upon detection of faults, a participatory clustering algorithm is used to classify these faults and tested to obtain the best set of parameters to achieve the most accurate clustering for these tests in the application being discussed in the article. [Copyright &y& Elsevier]

Abstract: It has been reported that treatment with tricin (4′,5,7-trihydroxy-3′,5′-dimethoxyflavone), a derivative of Sasa albo-marginata, after human cytomegalovirus (HCMV) infection significantly suppressed both infectious virus production and HCMV replication in the human embryonic fibroblast cell line MRC-5. In this paper, we examined the mechanisms for the anti-HCMV effects of tricin in MRC-5 cells. Exposure of fibroblasts to tricin inhibited infectious HCMV production, with concomitant decreases in levels of transcripts of the CXC chemokine IFN-inducible T cell alpha chemoattractant (I-TAC or CXCL11) gene. We also found that the transcripts of the HCMV immediate early (IE) gene and replication of HCMV were lower in CXCL11 gene-knockdown cells. These results suggest that tricin is a novel compound with potential anti-HCMV activity and that CXCL11 is one of the chemokines involved in HCMV replication. In addition, it is possible that CXCL11 is the one of the targets of tricin. [Copyright &y& Elsevier]

Abstract: The generation of both antibody and CD8+ T cell responses against pathogens is considered important for many advanced vaccines for diseases including tuberculosis, HIV and malaria. However, most current vaccines are delivered into muscle by the needle and syringe method and induce protection via humoral (antibody) immune responses. In this paper, we test the hypothesis that delivering a model subunit protein antigen (ovalbumin) to the skin''s abundant immune cell population using a densely packed microprojection array (Nanopatch) enhances CD8+ T cell responses. We found that the Nanopatch significantly enhanced the CD8+ T cell responses when compared to intramuscular delivery of both antigen-only and adjuvanted cases (Quil-A and CpG; separately). To our knowledge, this is the first published study demonstrating significantly improved CD8+ T cell responses achieved by delivering subunit vaccines to the skin''s abundant immune cell population. Successfully replicating these findings in humans could significantly advance the reach of vaccines. [Copyright &y& Elsevier]

Triggering receptor expressed on myeloid cells (TREM)-like transcript-1 (TLT-1) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-baring TREM family protein. In this study, we identified an alternative transcript form of TLT-1, namely TLT-1s, which has very short extracellular immunoglobulin domain consisting of only 202 amino acids. TLT-1s was mainly expressed in macrophages and osteoclast precursor cells. Upon receptor activator of nuclear factor-κB ligand stimulation, TLT-1s mRNA and protein levels were gradually decreased in BMMs. We also showed the TLT-1s is localized to the cytoplasmic membrane in osteoclast precursor cells. TLT-1s silencing strongly enhanced the formation and resorption activity of osteoclast. In addition, forced expression of TLT-1s showed reduced formation of osteoclast. Because ITIM-baring proteins inhibit immunoreceptor tyrosine-based activation motif (ITAM)-mediated receptor signaling, we tested whether TLT-1s physically interacted with TREM-2, the ITAM-associated co-stimulatory receptor essential for osteoclast differentiation. We showed that TLT-1s is associated with TREM-2 in osteoclast precursor cells. TLT-1s is also associated with tyrosine Src homology 2 domain-containing phosphatase-1 andSH2 domain-containing inositol phosphatase-1 and recruited them to the TREM2-ITAM signaling complex. In addition, knockdown of TLT-1s markedly elevated the intracellular calcium concentration and oscillation in osteoclast precursor cells. In addition, calcium-mediated induction of nuclear factor of activated T cells was also increased by TLT-1s silencing. Furthermore, TREM-2-mediated Akt activation and proliferation of osteoclast precursor cells were also enhanced in TLT-1s silenced cells. In this paper, we found the noble ITIM-baring inhibitory membrane protein; TLT-1s, which regulates ITAMmediated signaling on osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Abstract: In this paper we evaluate the role of human γδ T cells in control of Francisella tularensis infection. Using an in vitro model of infection, a reduction in bacterial numbers was detected in the presence of human γδ T cells for both attenuated LVS and virulent SCHU S4 strains of F. tularensis. Antibody neutralisation of IFN-γ caused an increase in survival of F. tularensis LVS suggesting that γδ T cell-mediated control of F. tularensis infection is partially mediated by IFN-γ. [Copyright &y& Elsevier]

Abstract: The development of the anti-CTLA-4 antibody (ipilimumab; marketed as Yervoy 1 [1] Yervoy is an FDA approved human anti-CTLA-4 monoclonal antibody developed by Bristol-Myers Squibb. ) immune regulatory therapy was based on the premise that “Abrogation of the function of CTLA-4 would permit CD28 to function unopposed and might swing the balance in favor of immune stimulation, tolerance breakdown and tumor eradication…” (). By now, the vast majority of data collected from more than 4000 patients proves that this prediction was entirely correct. Paradoxically, the successful blockade of immune checkpoints raises the question whether an anti-CTLA-4 antibody could ever become an important therapy against cancer. T cells lost their ability to discriminate between self and non-self. Thus, tolerance to self tissues was broken in ∼70% of the patients. In the recent industry-sponsored phase III clinical trial of ipilimumab, 147 (38.7%) of the patients experienced severe adverse events and 6.8% suffered dose-limiting events (8.4%, in the ipilimumab-alone group). There were 14 deaths related to the study drugs and 7 of these were associated with immune-related adverse events. In contrast, the complete response rate was only 0.2%, in one patient out of 403 who received ipilimumab plus a peptide vaccine. Promoters of ipilimumab appear to be unmindful of the clinical trial catastrophe in London. Then, a humanized “superagonist” anti-CD28 monoclonal antibody, TGN1412, which “preferentially” activated regulatory T cells, at a higher dose, also activated all CD28 positive T cells. This precipitated a “cytokine storm” leading to life-threatening multiple organ failure in the six healthy human volunteers. Neither anti-CD28 nor anti-CTLA-4 therapies rely on antigen-specificity. Both release free antibody into the body against common molecular targets that are expressed on the targeted as well as on the non-targeted T cells. At lower antibody doses specific T cells are preferentially activated. With increasing antibody dose, however, the kinetics of the interaction is pushed in favor of widespread non-specific T cell expansion. Using the law of mass action we calculated that the vast majority of the CTLA-4 receptors on all activated T cells (including melanoma specific T cells) in the phase III clinical trial of ipilimumab will have been saturated. This would explain the runaway immune response observed. The conclusions drawn by the authors of the ipilimumab trial paper could bear an independent inspection and reassessment concerning the validation of the blockade of immune checkpoints as an important therapeutic strategy against cancer. [Copyright &y& Elsevier]

Abstract: In this paper, we study a delayed six-dimensional human immunodeficiency virus (HIV) model with Cytotoxic T Lymphocytes (CTLs) immune response. Our model describes the interaction of HIV with two target cells: CD4+ T cells and macrophages. We derive that the global asymptotic attractivity of the model is completely determined by the basic reproduction number and the immune reproduction number for the viral infection. By constructing Lyapunov functionals, we have shown that the infection-free equilibrium , the immune-free equilibrium and the chronic-infection equilibrium are globally asymptotically attractive when and , respectively. [Copyright &y& Elsevier]

Abstract: Icaritin is a native compound from Epimedium Genus, a traditional Chinese herbal medicine which is effective in treating asthma, autoimmune diseases and viral infections. In the present paper, the immunosuppressive effects of icaritin were found through in vitro and in vivo studies. Icaritin could dose-dependently inhibit murine CD4+ T cells proliferation stimulated with mitogens or specific antigen ovabumin (OVA). Icaritin at 0.25–25μM could down-regulate T cell activation marker CD25 expression and inhibit IL-2 production. It could also reduce the Th1 cytokine IFN-γ production significantly if the T cells were activated by ConA or anti-CD3; while the inhibition of IL-4 secretion was only seen on anti-CD3 activated T cells treated with low concentrations of icaritin. In vivo study showed that treatment of icaritin at 10mg/kg/day on mice could suppress the immune response with prolonged allograft skin survival. Further study demonstrated that it reduced the alloantigen-induced splenocytes proliferation and Th1/Th2 cytokines. It could also increase NF-AT luciferase activity in Jurkat-NF-AT-luc T cells. The above results suggested that icaritin might be used to treat Th1 dominated immune diseases by interfering T cells activation with mechanism different to CsA. [Copyright &y& Elsevier]

Abstract: The enzyme purine nucleoside phosphorylase (PNP) is a target for the discovery of new lead compounds employed on the treatment severe T-cell mediated disorders. Within this context, the development of new, direct, and reliable methods for ligands screening is an important task. This paper describes the preparation of fused silica capillaries human PNP (HsPNP) immobilized enzyme reactor (IMER). The activity of the obtained IMER is monitored on line in a multidimensional liquid chromatography system, by the quantification of the product formed throughout the enzymatic reaction. The K M value for the immobilized enzyme was about twofold higher than that measured for the enzyme in solution (255±29.2μM and 133±14.9μM, respectively). A new fourth-generation immucillin derivative (DI4G; IC50 =40.6±0.36nM), previously identified and characterized in HsPNP free enzyme assays, was used to validate the IMER as a screening method for HsPNP ligands. The validated method was also used for mechanistic studies with this inhibitor. This new approach is a valuable tool to PNP ligand screening, since it directly measures the hypoxanthine released by inosine phosphorolysis, thus furnishing more reliable results than those one used in a coupled enzymatic spectrophotometric assay. [Copyright &y& Elsevier]

Abstract: In this paper, we study the dynamics of a mathematical model on primary and secondary cytotoxic T-lymphocyte (CTL) response to viral infections by Wodarz et al. This model has three equilibria and their stability criteria are discussed. The system transitions from one equilibrium to the next as the basic reproductive number, , increases. When increases even further, we analytically show that periodic solutions may arise from the third equilibrium via Hopf bifurcation. Numerical simulations of the model agree with the theoretical results and these dynamics occur within biologically realistic parameter range. The normal form theory is also applied to find the amplitude, phase and stability information on the limit cycles. Biological implications of the results are discussed. [Copyright &y& Elsevier]

Background: The immunosuppressive properties of regulatory T cells have emerged as an attractive tool for the development of immunotherapies in various disease contexts, e.g. to treat transplantation induced immune reactions. This paper focuses on the process of obtaining and functionally characterizing CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation. Methods: From October 2010 to March 2011 uremic patients awaiting living donor kidney transplantation, and their corresponding kidney donors, were enrolled in the study. A total of seven pairs were included. Isolation of CD4+CD25+FoxP3+ regulatory T cells was performed by magnetic activated cell sorting of peripheral blood mononuclear cells obtained from the uremic patients. Donor specific Trl cells were differentiated by repetitive stimulation of immature CD4+ T cells with immature dendritic cells, with the T cells coming from the future kidney recipients and the dendritic cells from the corresponding kidney donors. Cells were then expanded and functionally characterized by the one-way mixed leukocyte reaction and assessment of IL-10 production. Phenotypic analysis was performed by flow cytometry. Results: The fraction of CD4+CD25+FoxP3+ regulatory T cells after expansion varied from 39.1 to 50.4% and the cells retained their ability to substantially suppress the mixed leukocyte reaction in all but one patient (3.8-19.2% of the baseline stimulated leukocyte activity, p<0.05). Trl cells were successfully differentiated from all but one patient and produced high levels of IL-10 when stimulated with immature dendritic cells (1,275-11,038% of the baseline IL-10 secretion, p<0.05). Conclusion: It is practically feasible to obtain and subsequently expand CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients without loss of function as assessed by in vitro analyses. This forms a base for adoptive regulatory T cell therapy in the setting of living donor kidney transplantation. [ABSTRACT FROM AUTHOR]

Abstract: The microsporidia are emerging agents of infectious disease in both immunocompromised and immunocompetent mammals. Recently, there has been an increased interest in studying the immunobiology of microsporidiosis. This paper discusses the humoral and cell-mediated immune responses to Encephalitozoon spp. The T-cell-mediated responses appear to be most important in conferring resistance. This has become evident by the lethal effects of microsporidiosis in T-cell-deficient hosts. However, much still needs to be learned about the immunobiology of microsporidiosis regarding the specific T-cell responses and the cytokines that provide protective immunity and facilitate the macrophage-mediated killing of microsporidia. Such information will become important in developing immunotherapeutic strategies to control microsporidiosis in the future. [Copyright &y& Elsevier]

Abstract: In this paper, we consider an HIV pathogenesis model including cure rate and the full logistic proliferation term of CD4+ T cells in healthy and infected populations. Let be the number of virus released by each productive infected CD4+ T cell. The critical number that ensures the existence of the positive equilibrium is obtained. We further show that if , then there exists a unique uninfected equilibrium point that is locally asymptotically stable. If , then the system is persistent and the only infected steady state is globally asymptotically stable in the feasible region. Numerical simulations are presented to illustrate the obtained main results. Moreover, we find that there exist periodic solutions when the infected steady state is unstable. [Copyright &y& Elsevier]

Abstract: In this paper, the homotopy analysis method (HAM) is investigated to give an approximate solution of a model for HIV infection of CD4+ T-cells. This method allows for the solution of the governing differential equation to be calculated in the form of an infinite series with components which can be easily calculated. The HAM utilizes a simple method to adjust and control the convergence region of the infinite series solution by using an auxiliary parameter. The results obtained are presented, and six terms are sufficient to obtain an approximation solution that is very accurate. [Copyright &y& Elsevier]

Abstract: In this paper, a multi-step differential transform method (MsDTM) is performed to give approximate and analytical solutions of nonlinear fractional order ordinary differential equation systems such as a model for HIV infection of CD4+ T cells. The numerical solutions obtained from the proposed method indicate that the approach is easy to implement and accurate when applied to systems of fractional differential equations. Some figures are presented to show the reliability and simplicity of the methods. [Copyright &y& Elsevier]

Abstract: Influenza is one of the most common infectious diseases afflicting humans, particularly the elderly. The murine model has been widely employed for investigation of immunity to influenza virus infection. In this paper, we review the recent advances in understanding the diminished CD8 T cell immune response to influenza virus infection in aged mice. Possible mechanisms of impaired CD8 T cell responses with aging are addressed, including: (1) the role of dendritic cells (DCs); (2) the effect of age-associated changes in the T cell repertoire; and (3) the interactions with CD4 T cells, including T regulatory (Treg) cells and CD4 T helper cells. The aged murine model of the CD8 T cell response to influenza virus is helping to elucidate the mechanisms of immunosenescence which can lead to therapeutic improvements in the primary CD8 T cell response to new infections, as well as the development of new strategies for immunization to prevent influenza in the elderly. [Copyright &y& Elsevier]

Abstract: In this paper, a fractional order differential system for modeling human T-cell lymphotropic virus I (HTLV-I) infection of CD4+ T-cells is studied and its approximate solution is presented using a multi-step generalized differential transform method. The method is only a simple modification of the generalized differential transform method, in which it is treated as an algorithm in a sequence of small intervals (i.e. time step) for finding accurate approximate solutions to the corresponding systems. The solutions obtained are also presented graphically. [Copyright &y& Elsevier]

Abstract: In this paper, a mathematical model for HILV-I infection of CD4+ T-cells is investigated. The force of infection is assumed be of a function in general form, and the resulting incidence term contains, as special cases, the bilinear and the saturation incidences. The model can be seen as an extension of the model [Wang et al. Mathematical analysis of the global dynamics of a model for HTLV-I infection and ATL progression, Math. Biosci. 179 (2002) 207-217; Song, Li, Global stability and periodic solution of a model for HTLV-I infection and ATL progression, Appl. Math. Comput. 180(1) (2006) 401-410]. Mathematical analysis establishes that the global dynamics of T-cells infection is completely determined by a basic reproduction number . If , the infection-free equilibrium is globally stable; if , the unique infected equilibrium is globally stable in the interior of the feasible region. [Copyright &y& Elsevier]

Abstract: Establishment of a leukemia plasmacytoid dendritic cell line (PMDC05) and intra-lineage transformation from pDCs to mDCs in PMDC05 has been reported. In this paper, we show the applicability of PMDC05 for cellular immunotherapy. By stimulation with LPS, PMDC05 showed enhancement in expression of antigen presentation-associated surface molecules and production of cytokines (IL-12p70 and TNF-α). The antigen presenting ability was markedly increased in PMDC05 stimulated with LPS. By co-culturing of CD8+ T cells with LPS-stimulated and WT1/CMVpp65 peptide-pulsed PMDC05, WT1/CMVpp65 tetramer+ cytotoxic T lymphocytes were efficiently generated. These findings reveal the applicability of PMDC05 in cellular immunotherapy for tumor and severe viral infections. [Copyright &y& Elsevier]

Abstract: This paper reports the cloning and sequencing of interleukin (IL)-23 p19 subunit for the first time within a non-mammalian species, the zebrafish (Danio rerio), which was discovered using a synteny approach. In addition, amino acid sequences were for IL-23 p19 subunits were also predicted from the stickleback, Fugu and Tetraodon genomes and included in this investigation. The zebrafish IL-23 p19 cDNA consisted of a 66bp 5′ UTR, a 249bp 3′ UTR and a single open reading frame of 567bp giving a predicted 188 aa IL-23 p19 molecule. Multiple alignment of zebrafish IL-23 p19, with other known IL-23 p19 and IL-12 p35 amino acid sequences revealed areas of amino acid conservation, such as the presence of four predicted α-helixes, cysteines important for disulphide bond formation and the conservation of a tryptophan known to interact with the receptor. Amino acid homologies and phylogenetic analysis confirmed the relationship of the fish IL-23 p19 subunits with their mammalian homologues. All the teleost fish IL-23 p19 subunits were found to have 4 exons and 3 introns similar to that of human and mouse IL-23 p19 and a limited degree of synteny was found between the organisms for the regions containing the IL-23 p19 genes with only PAB-dependent poly(A)-specific ribonuclease subunit 2 (PAN2) and IL-23 p19 found in the same order on human chromosome 12 and all the fish genomes looked at. Lastly using real-time PCR, constitutive expression of IL-12 p40 and IL-23 p19 was observed in the kidney, liver, gut and muscle with IL-12 p40 expression higher than IL-23 p19. As soon as an hour after stimulation with LPS, there was an increase of IL-23 p19 in zebrafish leukocytes and an increase of IL-1β, IL-12 p40 and IL-23 p19 expression was found after infection of zebrafish for 1 or 6 days with Mycobaterium marinum strain E11. [Copyright &y& Elsevier]

The high failure rate of immunotherapies in multiple sclerosis (MS) clinical trials demonstrates problems in translating new treatment concepts from animal models to the patient. One main reason for this ‘immunotherapy gap’ is the usage of immunologically immature, microbiologically clean and genetically homogeneous rodent strains. Another reason is the artificial nature of the experimental autoimmune encephalomyelitis model, which favors CD4+ T cell driven autoimmune mechanisms, whereas CD8+ T cells are prevalent in MS lesions. In this paper, we discuss preclinical models in humanized rodents and non-human primates that are genetically closer to MS. We also discuss models that best reproduce specific aspects of MS pathology and how these can potentially improve preclinical selection of promising therapies from the discovery pipeline. [ABSTRACT FROM AUTHOR]

Abstract: For decades Experimental Autoimmune Encephalitis (EAE) has remained as an unsurpassed multiple sclerosis (MS) animal model. C-Phycocyanin (C-Pc) has been reported to exhibit pharmacological properties that may be expected to symptomatically improve EAE and MS. However, in this paper we reveal a basic underlying mechanism that may provide a new approach to the rationale of the overall beneficial effect of this natural antioxidant. We demonstrate that C-Pc is able to trigger mechanisms preventing or downgrading EAE expression and induces a regulatory T cell (Treg) response, in peripheral blood mononuclear cells (PBMC) from MS patients. These results agree with reports suggesting that Treg limit acute MS attacks and that C-Pc may act as a neuroprotector and thereby reverts the organic and functional damage in neurodegenerative disorders of the central nervous system (CNS). Moreover, evidence is provided on the antioxidant activity of C-Pc within the CNS, intended to improve the myelin and axonal damage of EAE induced Lewis rats. Our results indicate that specific Treg activation may represent a central and essential mechanism in supporting the therapeutic potential of C-Pc for MS and may lead to new and more effective therapies; this property would then complement and enhance other proven active principles such as interferons (IFN), giving rise to combined therapies. [ABSTRACT FROM AUTHOR]

Abstract: Food allergy is a significant health issue in the UK, affecting between 1 and 2% of adults and 5 and 8% of children. The UK Food Standards Agency seeks to ensure the safety of food allergic consumers by providing them with information and guidance on food choices. Since 1995, with the aim of addressing important policy issues and improving the quality of the support and guidance available for food allergic consumers, the Agency (and before that the Ministry of Agriculture, Fisheries and Food), has had a programme of research dedicated to investigating the causes and mechanisms of food allergy and delivering benefits for UK consumers. In this paper, we outline some of the major scientific challenges that the programme has sought to address. We reflect on how the findings have been used as a basis for the development of sound, evidence-based policy and advice for UK consumers, and the current direction of research being supported by the programme. [ABSTRACT FROM AUTHOR]

The major pathway for HIV internalization in CD4+ T cells has been thought to be the direct fusion of virus and cell membranes, because the cell surface is the point of entry of infectious particles. However, the exact contribution of endocytic pathways to the infection of CD4+ T lymphocytes is unknown, and the mechanisms involved in endocytosis of HIV particles are unclear. Recent evidence suggests that endocytosis of cell-free and cell-associated virus particles could lead to effective virus entry and productive infections. Such observations have, in turn, spurred a debate on the relevance of endosomal entry as a mechanism of escape from the immune system and HIV entry inhibitors. In this paper, we review the endocytosis of HIV and discuss its role in HIV infection and pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: The immune system has evolved to coordinate responses against numerous invading pathogens and simultaneously remain silent facing self-antigens and those derived from commensal organisms. But, if both processes are not maintained in strict balance, a potential threat can emerge due to the risk of chronic inflammation and/or autoimmunity development. Therefore, there is a negative immune regulation where tolerogenic dendritic cells (tDCs) participate actively. Under steady-state conditions, tDC are notably involved in the elimination of autoreactive T cells at the thymus, and in the control of T cells specific to self and harmless antigens in the periphery. But in the presence of foreign antigens in an inflammatory milieu, dendritic cells (DCs) mature and induce T cells activation and their migration to B cell areas to assist in antibody production. Additionally, there are other factors such as infections, anti tumoral immune responses, trauma-mediated disruption, etc. that may induce alterations in the balance between tolerogenic and immunogenic functions of DCs and instigate the development of autoimmune diseases (ADs). Therefore, in recent years, DCs have emerged as therapeutic targets to control of ADs. Diverse strategies in vitro and/or in animal models of ADs have explored the tolerogenic functions of DCs and demonstrated their feasibility to prevent or control an autoimmune process, but still leaving a void in their application in clinical assays. The purpose of this paper is to give a general overview of the current literature on the significance of tDCs in tolerance maintenance to self and innocuous antigens, the most relevant alterations involved in the pathophysiology of ADs, the cellular and molecular mechanisms involved in their tolerogenic function and the current strategies used to exploit their tolerogenic potential. [Copyright &y& Elsevier]

Abstract: Cytokine secretion by leukocytes is an important indicator of immune response to pathogens and therefore has significant implications in disease diagnostics. Given heterogeneity of leukocyte subsets and the ability of multiple cell subsets to secrete the same cytokines, connecting cytokine production to a specific leukocyte subset is a distinct challenge. In the present paper we describe a strategy combining antibody (Ab)-based affinity cell separation and surface plasmon resonance (SPR) for capturing human CD4 T-cells and for label-free detection of cell-secreted interferon (IFN)-γ – an important inflammatory cytokine. Human blood was introduced into a flow chamber modified with anti-CD4 Abs resulting in capture of CD4+ T-cells. After mitogenic activation of cells inside the flow chamber, culture medium was routed onto an SPR chip modified with monoclonal IFN-γ Abs. SPR signal observed in this experiment correlated with cytokine production by T-cells. The strategy of combining SPR detection with cell purification may be used in the future for label-free, sensitive detection of multiple cytokines or proteins secreted by the desired cell subset. [Copyright &y& Elsevier]

Abstract: The capability of the HIV to persist latent inside CD4+ T-cells is currently regarded as a barrier to recovery from infection. On the other hand, immune activation, which is a normal immune reaction to pathogens, is now recognized as a key ingredient to sustaining the HIV caused infection. Further, it has been shown that activation of infected memory T-cells indirectly promotes apoptosis (programmed cell death) of bystander CD4+ and CD8+ T-cells. In this paper we use standard modeling techniques to develop a model compliant with the above mentioned mechanisms. Our farthest goal is to study how the long-term depletion of T-cells that characterizes HIV pathogenesis depends on these mechanisms. Consequently, we conduct parameter estimation, and apply standard results of sensitivity analysis and principal component analysis of the state variables with respect to the parameters. [ABSTRACT FROM AUTHOR]

Abstract: A current study shows that sodium dichloroacetate (DCA) can induce cancer cell apoptosis and inhibit tumor growth, but its cytotoxic activity is low (IC50 > 1000 μM for A549). In this paper, a variety of DCA derivatives were synthesized, and their cytotoxic activities were evaluated. The result showed that the N-phenyl-2,2-dichloroacetamide analogues had satisfactory potencies. Among them, N-(3-iodophenyl)-2,2-dichloroacetamide (3e), an optimized lead compound, has an IC50 against A549 as low as 4.76 μM. Furthermore, it can induce cancer cell apoptosis and has a low toxicity in mice (LD50 = 1117 mg/kg). [ABSTRACT FROM AUTHOR]

How the fetal ‘allograft’ avoids rejection during pregnancy remains a major unresolved immunological paradox. Recent work has suggested that fetomaternal tolerance is in fact maintained by a number of redundant mechanisms, but their relative importance has remained poorly defined. In this paper, I discuss an emerging controversy regarding the ability of maternal T cells to mediate fetal rejection at a time when they appear to be ignorant of fetal and placental antigens. This paradox within a paradox highlights two major research directions in the field of reproductive immunology that, when ultimately reconciled, promise to give significant insight into mechanisms of impaired fertility and compromised fetal and maternal health. [Copyright &y& Elsevier]