Search

Background.Studies indicate that following septic insult there is development of generalized immune dysfunction in T cells, B cells and phagocytes, which is thought to contribute to morbidity and mortality. Specifically, there is a shift in the lymphocytes of septic animals toward an increased release of Th2 cytokines. NK-T cells have been shown to contribute to propagation of the Th2 response. The influence of NK-T cells on the immune response to septic challenge is poorly understood. In this study, we examine whether NK-T cells contribute to the immune dysfunction seen following the onset of polymicrobial sepsis, as produced by cecal ligation and puncture (CLP).Materials and methods.Male 129S1/SvImJ mice were pretreated with either rat IgG (isotypic control) or monoclonal antibody to CD1d (clone 1B1) (0.5 mg), which blocks signaling/antigen presentation via the CD1d cell surface receptor, thereby, ablating the activation and differentiation of the NK-T cells. Septic survival with and without anti-CD1d (CLP/CD1d) pretreatment was assessed. Mice sacrificed 24 h after CLP were assessed for change in splenic %NK-T cell (via flourescense activated cell sector) and for splenic, hepatic, and lymphoid/macrophage production of pro-inflammatory or anti-inflammatory cytokines (via enzyme-linked immunosorbent assay).Results.Administration of anti-CD1d reduced septic mortality 35% at 6–10 d (n = 23 mice/group) (P < .05). There was a consistent increase in the %CD3+ NK1.1+ cell population (NK-T cells) in septic mice (1.706%), which was markedly suppressed by pretreatment with anti-CD1d (0.592%). IL-6 and IL-10 levels were suppressed by anti-CD1d in the spleen and blood.Conclusions.Together these findings imply not only that NK-T cells may play a role in mediating the immune suppression seen in bacterial sepsis, but that inhibition of their activation promotes survival to septic challenge. [Copyright &y& Elsevier]

• FOXP3 controls Treg differentiation and activity. • FOXP3 induces metabolic versatility in intra-tumoral Tregs. • Treg subsets show different reliance on FOXP3. Dysregulation of regulatory T cells (Tregs) is described in the context of inflammatory and autoimmune diseases, and cancer. Forkhead box P3 (FOXP3) is a transcription factor that its activity is an indicator of Treg identity. FOXP3 induces metabolic versatility in intra-tumoral Tregs, so that its deficiency mediates Treg instability or even gives rise to the acquisition of effector T cell phenotype. FOXP3 dysregulation and defectiveness occurs upon ubiquitination, methylation and presumably acetylation. Stimulators of PTEN, mammalian target of rapamycin complex 2 (mTORC2), and nucleus accumbens–associated protein-1 (NAC1), and inhibitors of B lymphocyte-induced maturation protein-1 (Blimp-1), Deltex1 (DTX1) and ubiquitin-specific peptidase 22 (USP22) are suggested to hamper FOXP3 stability, and to promote its downregulation and further Treg depletion. A point is that Treg subsets reveal different reliance on FOXP3, which indicates that not all Tregs are strictly dependent on FOXP3, and presumably Tregs with different origin rely on diverse regulators of FOXP3 stability. The focus of this review is over the current understanding toward FOXP3, its activity in Tregs and influence from different regulators within tumor microenvironment (TME). Implication of FOXP3 targeting in cancer immunotherapy is another focus of this paper. [ABSTRACT FROM AUTHOR]

CD28 and CD80/86 are crucial co-stimulatory molecules for the T cell activation. Previous study illustrated that CD28 and CD80/86 present on T cells and antigen-presenting cells in flounder (Paralichthys olivaceus), respectively. The co-stimulatory molecules were closely associated with cell immunity. In this paper, recombinant protein of flounder CD80/86 (rCD80/86) and phytohemagglutinin (PHA) were added to peripheral blood leukocytes (PBLs) in vitro. Lymphocytes were significantly proliferated with CFSE staining, and the proportion of CD4+ and CD28+ lymphocytes significantly increased. In the meantime, genes related to the CD28-CD80/86 signaling pathway or T cell markers were significantly upregulated (p < 0.05). For further study, the interaction between CD80/86 and CD28 was confirmed. The plasmid of CD28 (pCD28-FLAG and pVN-CD28) or CD80/86 (pVC-CD80/86) was successfully constructed. In addition, pVN-ΔCD28 without the conserved motif "TFPPPF" was constructed. The results showed that bands of pCD28-FLAG bound to rCD80/86 were detected by both anti-FLAG and anti-CD80/86. pVN-CD28 complemented to pVC-CD80/86 showing positive fluorescent signals, and pVN-ΔCD28 failed to combine with pVC-CD80/86. The motif "TFPPPF" in CD28 played a crucial role in this linkage. These results indicate that CD28 and CD80/86 molecules interact with each other, and their binding may modulate T lymphocytes immune response in flounder. This study proved the existence of CD28-CD80/86 signaling pathway in flounder. • RCD80/86 and PHA induced lymphocyte proliferation and proportion of CD4+ cells in flounder. • RCD80/86 and PHA upregulated the expression of B7-CD28 signaling pathway genes, T cell markers, and cytokines. • PCD28-FLAG bound to rCD80/86, and pVN-CD28 complemented to pVC-CD80/86 in vitro. • Motif of "TFPPPF" in CD28 plays crucial role in the interaction between CD28 and CD80/86. [ABSTRACT FROM AUTHOR]

Interleukin-2 receptor (IL-2R), as the specific ligand of interleukin-2 (IL-2), binds to IL-2 and transmits signals and then can induce the proliferation of T lymphocytes in mammals. In this paper, the subunit of IL-2R in flounder (Paralichthys olivaceus), interleukin-2 receptor subunit gamma (IL-2Rγ) was cloned, and polyclonal antibodies (Abs) against its extracellular region were produced, then the expression of flounder IL-2Rγ (fIL-2Rγ) at transcriptional and cellular levels were characterized. Moreover, the interaction of flounder IL-2 (fIL-2) with fIL-2Rγ was investigated, and the variations on CD4+/IL-2Rγ+ cells in flounder after treatment with recombinant IL-2 (rIL-2), anti-IL-2Rγ Abs were detected, respectively. The results showed that fIL-2Rγ protein had a typical fibronectin type III (FN3) domain. The Abs could specifically recognize native fIL-2Rγ molecules at 39.9 kDa. FIL-2Rγ was localized on both T and B lymphocytes, and the percentages of CD4+/IL-2Rγ+ and IgM+/IL-2Rγ+ lymphocytes were high in spleen. In addition, pBiFC-VN173-IL-2Rγ plasmids could bind to pBiFC-VC155-IL-2 plasmids. The percentage of CD4+/IL-2Rγ+ lymphocytes was significantly decreased after blocking with anti-IL-2Rγ Abs both in vivo and in vitro. In the meantime, four T cell markers genes and six IL-2-IL-2R pathway genes were down-regulated in anti-IL-2Rγ Abs group. These results first demonstrated that fIL-2Rγ molecules were expressed on both T and B lymphocytes in flounder, and the bond between fIL-2Rγ and fIL-2 activated the CD4 T lymphocytes. This study gave a new sight into the exploration of IL-2R function on T lymphocytes proliferation in fish. • IL-2Rγ mRNA was highly expressed in peripheral blood leukocytes, spleen and head kidney in flounder. • IL-2Rγ molecules were localized on both T and B lymphocytes in flounder. • Flounder IL-2 could bind to flounder IL-2Rγ. • The addition of recombinant IL-2 significantly increased the percentage of CD4+/IL-2Rγ+ lymphocytes at 72 h. [ABSTRACT FROM AUTHOR]

Immunological memory can be regarded as the key aspect of adaptive immunity, i.e. a specific response to first contact with an antigen, which in mammals is determined by the properties of T, B and NK cells. Re-exposure to the same antigen results in a more rapid response of the activated specific cells, which have a unique property that is the immunological memory acquired upon first contact with the antigen. Such a state of immune activity is also to be understood as related to "altered behavior of the immune system" due to genetic alterations, presumably maintained independently of the antigen. It also indicates a possible alternative mechanism of maintaining the immune state at a low level of the immune response, "directed" by an antigen or dependent on an antigen, associated with repeated exposure to the same antigen from time to time, as well as the concept of innate immune memory, associated with epigenetic reprogramming of myeloid cells, i.e. macrophages and NK cells. Studies on Teleostei have provided evidence for the presence of immunological memory determined by T and B cells and a secondary response stronger than the primary response. Research has also demonstrated that in these animals macrophages and NK-like cells (similar to mammalian NK cells) are able to respond when re-exposed to the same antigen. Regardless of previous reports on immunological memory in teleost fish, many reactions and mechanisms related to this ability require further investigation. The very nature of immunological memory and the activity of cells involved in this process, in particular macrophages and NK-like cells, need to be explained. This paper presents problems associated with adaptive and innate immune memory in teleost fish and characteristics of cells associated with this ability. • The presence of adaptive and innate immune memory has been confirmed in fish. • Adaptive immune memory in fish develops with the participation of T and B lymphocytes. • Innate immune memory is related to the properties of macrophages and NK-like cells. • There is a need to further verify the biological basis of this property. [ABSTRACT FROM AUTHOR]

Highlights • This is the first mathematical model of RA which quantitatively describes the progression of the disease. • The model explains the roles of macrophages, inflammatory fibroblasts, and T cells in the degradation of cartilage in a joint. • Example is given how to achieve the same efficacy in stabilization of the cartilage while decreasing negative side-effects. Abstract Rheumatoid arthritis (RA) is a common autoimmune disease that mainly affects the joints. It is characterized by synovial inflammation, which may result in cartilage and bone destruction. The present paper develops a mathematical model of chronic RA. The model is represented by a system of partial differential equations (PDEs) in the synovial fluid, the synovial membrane, and the cartilage. The model characterizes the progression of the disease in terms of the degradation of the cartilage. More precisely, we assume a simplified geometry in which the synovial membrane and the cartilage are planar layers adjacent to each other. We then quantify the state of the disease by how much the cartilage layer has decreased, or, equivalently, how much the synovial layer has increased. The model is used to evaluate treatments of RA by currently used drugs, as well as by experimental drugs. [ABSTRACT FROM AUTHOR]

Abstract In order to elucidate the influence of T lymphocytes subpopulations on B lymphocytes immune response, in this paper, CD4-1+, CD4-2+, CD8+ T lymphocytes and B lymphocytes responses to thymus-independent (TI) or thymus-dependent (TD) antigen plus immunosuppressant were investigated in flounder (Paralichthys olivaceus). The results showed that in LPS-immunized group, the percentages of CD4-1+, CD4-2+, CD8β+ T (PCD4-1+ T, PCD4-2+ T and PCD8β+ T) lymphocytes in peripheral blood leucocytes (PBLs) had no significant variations, the percentages of IgM+ B (PIgM+ B) lymphocytes and LPS-specific antibodies (LA) significantly increased and peaked at 3rd or 4th week post-injection; CsA had no inhibition on both T/B lymphocytes and LA; RaPa only suppressed the PIgM+ B lymphocytes and LA, and the inhibition maximum (Imax) were about 35% and 20%, respectively. In KLH-immunized group, the PCD4-1+, PCD4-2+ and PCD8β+ T lymphocytes significantly increased and peaked at 3rd or 5th day, successively the PIgM+ B lymphocytes and KLH-specific antibodies (KA) significantly increased to the peak at 5th week; the PCD4-1+, PCD4-2+ T and PIgM+ B lymphocytes and LA were inhibited significantly by both CsA and RaPa, and the Imax on them were 13%–33%, 11%–25%, 19%–34%, 22%–26%, respectively, while the PCD8β+ T lymphocytes showed no significant suppression. The results indicated that the suppression of PIgM+ B lymphocytes in KLH + CsA group was not directly derived from CsA, but due to the suppression of T lymphocytes, especially CD4+ T lymphocytes subpopulations. The results showed for the first time that, similar to higher vertebrates, T lymphocytes didn't respond to TI antigen, moreover, T lymphocyte subpopulations had a regulation on the immune response of B lymphocyte for TD antigen in flounder. Highlights • KLH activated CD4-1+, CD4-2+, CD8+ T and B lymphocytes responses. • LPS only induced B lymphocytes response and antibodies production. • Cyclosporine A (CsA) specifically inhibited T lymphocytes. • CD4-1+, CD4-2+ T lymphocytes influenced the response of B lymphocytes for TD antigen. [ABSTRACT FROM AUTHOR]

• A model is proposed based on the key role of Regulatory T cells in chemoimmunotherapy. • The model's fixed points are obtained and the bifurcation diagrams are discussed. • New features of personalizing a cancer mathematical model are presented. • Considering Regulatory T cells leads to identifying critical patient conditions more precisely. Studying the mathematical dynamics of cancer has gained the attention of bioengineers in the past three decades. Different kinds of modelling considering various aspects of treatment have been proposed. In this paper, the key role of Regulatory T cells is discussed and a model in ordinary differential equation (ODE) form is proposed by adding this state to the system dynamics considering chemoimmunotherapy treatment. Regulatory T cells are considered as one of the main tumor cells' tactics to deceive the body's immune system. The improved model is verified mathematically and biologically and fits all criteria in both fields. The results show that entering Regulatory T cells state on cancer mathematical modelling for simulating body cells for chemoimmunotherapy provides a way to identify critical cases more carefully, which a simplified model is unable to accomplish. This point emphasizes the fact that this state must be present in cancer modelling to anticipate immune response more accurately. The advanced system fixed points are obtained by the Newton method and bifurcation diagrams are derived and discussed. New features and remarks are proposed during the journey of developing more accurate models that have the best fit with laboratory data. The sensitivity chart of the model is illustrated and novel aspects of discussions are made with the aim of personalizing a model for a patient and identifying critical conditions based on the chart before any treatment begins. This point enables physicians to determine whether critical conditions have occurred for a patient in a specific treatment or not. [ABSTRACT FROM AUTHOR]

This paper summarizes and reviews the mechanisms of action and data concerning efficacy of recommended treatments as well as other treatments that have been tested, independently of the outcomes, in the management of chronic spontaneous urticaria. Due to the central role of mast cells, basophils and histamine in the pathophysiology of this disease, H 1 -antihistamines remain the first-line treatment. However, current knowledge about this complex disease, also recognizes an important role for T lymphocytes, B lymphocytes, and autoantibodies. Implications of these others mediators thus provide further targets for treatment. Indeed, agents previously used to treat other autoimmune and inflammatory diseases, have demonstrated efficacy in chronic spontaneous urticaria and are therefore potential therapeutic alternatives for antihistamine unresponsive patients. [ABSTRACT FROM AUTHOR]

In acquired immunity, T lymphocytes regulate the immune responses of B lymphocytes, including the IgM + B lymphocyte counts and antibody production. In this paper, Cyclosporine A (CsA) and Rapamycin (RaPa) were used, and their inhibition on T lymphocytes and immune responses of B lymphocytes in flounder ( Paralichthys olivaceus ) were investigated. Flounder was injected with Keyhole Limpet Hemocyanin (KLH), a mixture of KLH and CsA (KLH + CsA), or a mixture of KLH and RaPa (KLH + RaPa). Then, the proportions of T and IgM + B lymphocytes (PT and PB) in peripheral blood leukocytes (PBL) were analysed by flow cytometry (FCM), total antibodies (TA) and KLH specific antibodies (KA) in serum were measured by ELISA, and expression of 9 immune-related genes in the spleen and kidneys were determined using q-PCR. On the other hand, the PBL culture was treated with Concanavalin A (ConA), a mixture of ConA and CsA, and a mixture of ConA and RaPa. Then the PT and PB were measured, and the cell proliferation was examined using the MTT method. The results showed that the PT peaked on the 5 th day in the KLH group, KLH + CsA group and KLH + RaPa group. The maximum inhibition rates (MIR) of CsA and RaPa were 27.44% ± 0.50% and 21.37% ± 2.06%, respectively. The PB peaked at the 5 th week, and the MIR of CsA and RaPa were 44.51% ± 1.36% and 33.3% ± 0.65%, respectively. The KA and TA peaked at the 5 th week. The MIR of CsA and RaPa on TA were 40.31% ± 1.59% and 32.96% ± 2.21%, respectively, and were 27.77% ± 2.02% and 23.41% ± 1.08% for KA, respectively. Nine immune-related genes had significantly lower expression in the KLH + CsA group and KLH + RaPa group compared to the KLH group. The proliferation of the PBL culture was inhibited by CsA or RaPa, and the inhibition rate of CsA and RaPa for PT was 18.14% ± 1.08% and 17.88% ± 1.02%, respectively, and the inhibition rates for PB were 3.03% ± 0.57% and 2.95% ± 0.53%, respectively. The results demonstrated that T lymphocytes counts were inhibited by CsA and RaPa, followed by suppression of IgM + B lymphocytes and antibody production, which suggests that T lymphocytes regulate the immune response of B lymphocytes in flounder. [ABSTRACT FROM AUTHOR]

Various categories of coronavirus disease 19 (COVID-19) patients have exhibited major mortality rate differences and symptoms. Some papers have recently explained these differences in mortality rates and symptoms as a consequence of this virus infection acting in synergy with one or more latent pathogen infections in some patients. A latent pathogen infection likely to be involved in millions of these patients is the protozoan parasite Toxoplasma gondii , which infects approximately one third of the global human population. However, other papers have concluded that latent protozoan parasite infections can reduce the severity of viral infections. The aims and purposes of this paper include providing explanations for the contradictions between these studies and introducing a significant new category of T-cell exhaustion. Latent pathogens can have different genetic strains with great differences in their effects on a second pathogen infection. Furthermore, depending on the timing and effectiveness of drug treatments, pathogen infections that become latent may or may not later induce immune cell dysfunctions, including T-cell exhaustion. Concurrent multiple pathogen T-cell exhaustion is herein called "polyspecific T-cell exhaustion." • COVID-19 patients exhibit mortality rate differences probably from latent pathogen infections. • Toxoplasma gondii infects about one third of the global human population and it is likely involved. • Latent pathogens have different genetic strains & different effects on later pathogen infections. • Drug treatments affect pathogen infections causing immune dysfunctions, e.g. T-cell exhaustion. • "Polyspecific T-cell exhaustion" enables concurrent multiple pathogen T-cell exhaustion. [ABSTRACT FROM AUTHOR]

The newly discovered subset of memory T cells, tissue resident memory T (TRM) cells, reside in peripheral tissues for a long time, contributing to a rapid immune response and constituting the first line of defense when pathogens invade cells. Tissue resident memory T cells have unique transcriptome characteristics, and their presence in peripheral tissues is regulated by many factors. TRM cells residing in different tissues often express different surface markers. In addition to CD8+ and CD4+ T cells, which are the best-characterized T cells, Treg cells and various innate T cells can reside in nonlymphoid tissues. Many recent studies have shown that tissue resident memory T cells play indispensable roles in tumor immunity and allergic diseases. This paper reviews the differentiation, regulation, variety and function of TRM cells and the roles they play in skin diseases, including cutaneous melanoma and psoriasis. • Tissue-resident memory T cells exhibit distinct tissue-specific and niche-specific functions in immune detection network. • Multiple factors control the development and resident of Tissue-resident memory T cell. • Tissue-resident memory T cells participate in skin inflammation and contribute tomaintaining the recurrence of skin diseases. [ABSTRACT FROM AUTHOR]

Psoriasis is a common inflammatory skin disease involving interactions between keratinocytes and immune cells that significantly affects the quality of life. It is characterized by hyperproliferation and abnormal differentiation of keratinocytes and excessive infiltration of immune cells in the dermis and epidermis. The immune mechanism underlying this disease has been elucidated in the past few years. Research shows that psoriasis is regulated by the complex interactions among immune cells, such as keratinocytes, dendritic cells, T lymphocytes, neutrophils, macrophages, natural killer cells, mast cells, and other immune cells. An increasing number of signaling pathways have been found to be involved in the pathogenesis of psoriasis, which has prompted the search for new treatment targets. In the past decades, studies on the pathogenesis of psoriasis have focused on the development of targeted and highly effective therapies. In this review, we have discussed the relationship between various types of immune cells and psoriasis and summarized the major signaling pathways involved in the pathogenesis of psoriasis, including the PI3K/AKT/mTOR, JAK-STAT, JNK, and WNT pathways. In addition, we have discussed the results of the latest omics research on psoriasis and the epigenetics of the disease, which provide insights regarding its pathogenesis and therapeutic prospects; we have also summarized its treatment strategies and observations of clinical trials. In this paper, the various aspects of psoriasis are described in detail, and the limitations of the current treatment methods are emphasized. It is necessary to improve and innovate treatment methods from the molecular level of pathogenesis, and further provide new ideas for the treatment and research of psoriasis. • The relationship between various immune cells and psoriasis is discussed. • Major signaling pathways involved in the pathogenesis of psoriasis are summarized. • Results of the latest omics research on psoriasis are discussed. • Treatment strategies and clinical trial observations for psoriasis are summarized. [ABSTRACT FROM AUTHOR]

Abstract: Three years ago, the Journal of Autoimmunity and Autoimmunity Reviews launched a series of special issues devoted to the contributions of outstanding scholars in autoimmunology. The special issues are devoted not only to recognize achievements, but also to include a series of dedicated papers that reflect the scholar’s work, but also are cutting-edge research and reviews in immunology. This special issue is devoted to Haralampos M. Moutsopoulos of the National University of Athens. His contributions to patient care, teaching, and original research are legion. The papers that are included reflect not only a wide range of scholarship in autoimmunology, but importantly are written by his colleagues and friends, and by former students. They encompass original scholarship in Sjögren’s syndrome, but also in a number of effector pathways in both adult and pediatric autoimmunology. [ABSTRACT FROM AUTHOR]

We recently reported that blockade of IL-10 signalling at the time of a human papillomavirus (HPV) long E7 peptide/LPS immunization leads to the regression of established HPV-16 immortalized tumours in mice similar to that induced by long E7 peptide/incomplete Freund’s adjuvant (IFA)-based vaccination. In this paper, we demonstrated that blockade of IL-10 signalling at the time of long E7 peptide/LPS could elicit stronger T cells responses and render the tumour more accessible for immune cell infiltration than vaccination with long E7 peptide/IFA. Furthermore, priming with long E7 peptide/LPS and IL10 signalling blockade then boosting with long E7 peptide/IFA elicits stronger CD8+ T cell responses than long E7 peptide/IFA immunization. The results suggest that priming with long E7 peptide/LPS and IL10 signalling inhibitor, then boosting with long E7 peptide/IFA elicits may lead to better HPV infection related tumour regression in clinic. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a T cell-mediated organ-specific autoimmune disease. Antigen-specific immune intervention allows the selective targeting of autoreactive T cell, while leaving the remainder of the immune system intact. However, immune intervention for type 1 diabetes has not yielded perfect results clinically. In our paper published previously, we asked whether pancreatic duodenal home box 1 (PDX1) is a target of anti-islet autoimmunity in type 1 diabetes. In this experiment, we assessed the therapeutic effect of oral administration of PDX1 on diabetes development of 4-week-old non-obese diabetic (NOD) mice. The results indicate that PDX1 immunization is an effective intervention strategy for delaying the onset of diabetes in NOD mice in association with: 1) reduced insulitis; 2) suppression of destructive autoreactive T cells; 3) augmentation of regulatory T cells; 4) a shift in cytokine production. The present observations suggest that immunization with PDX1 modulates immune cell responses in NOD mice, raising the possibility that it is beneficial in ameliorating autoimmune destruction of beta-cells and delaying type 1 diabetes development clinically. [ABSTRACT FROM AUTHOR]

• In this paper, by reviewing MC phagocytic function, activated MC expression of APC surface markers, and MC participation in the inflammatory response and local renal immune response, we confirm that activated MCs can act as APCs in renal disease. • This review introduces MC function through a developmental perspective and summarizes the important role of MC as antigen-presenting cells in renal local immune response. • This review mentions the uniqueness of MC and also points out the limitations of MC research at this stage. Mesangial cells (MCs), as resident cells of the kidneys, play an important role in maintaining glomerular function. MCs are located between the capillary loops of the glomeruli and mainly support the capillary plexus, constrict blood vessels, extracellular matrix components, produce cytokines, and perform phagocytosis and clearance of macromolecular substances. When the glomerular environment changes, MCs are often affected, which can lead to functional transformation. The immune response is involved in the occurrence and development of various kidney diseases, in these diseases, antigen-presenting cells (APCs) play an important role. APCs can present antigens to T lymphocytes, causing them to become activated and proliferate. Studies have shown that MCs have phagocytic function and express APC markers on the cell surface. Additionally, MCs are stimulated by or produce various inflammatory factors to participate in the renal inflammatory response. Therefore, MCs have potential antigen presentation function and participate in the pathological changes of various kidney diseases as APCs upon activation. In this paper, by reviewing MC phagocytic function, activated MC expression of APC surface markers, and MC participation in the inflammatory response and local renal immune response, we confirm that activated MCs can act as APCs in renal disease. [ABSTRACT FROM AUTHOR]

• An individual-based model describing interactions between tumour and CD8+ T cells. • The model takes into account tumour antigen expression and presentation. • The degree of tumour heterogeneity has an impact on immune response efficacy. • Wider ranges of antigens promote immune escape of tumours. • Lower levels of antigen presentation diminish the immune action. Intra-tumour heterogeneity (ITH) has a strong impact on the efficacy of the immune response against solid tumours. The number of sub-populations of cancer cells expressing different antigens and the percentage of immunogenic cells (i.e. tumour cells that are effectively targeted by immune cells) in a tumour are both expressions of ITH. Here, we present a spatially explicit stochastic individual-based model of the interaction dynamics between tumour cells and CD8+ T cells, which makes it possible to dissect out the specific impact of these two expressions of ITH on anti-tumour immune response. The set-up of numerical simulations of the model is defined so as to mimic scenarios considered in previous experimental studies. Moreover, the ability of the model to qualitatively reproduce experimental observations of successful and unsuccessful immune surveillance is demonstrated. First, the results of numerical simulations of this model indicate that the presence of a larger number of sub-populations of tumour cells that express different antigens is associated with a reduced ability of CD8+ T cells to mount an effective anti-tumour immune response. Secondly, the presence of a larger percentage of tumour cells that are not effectively targeted by CD8+ T cells may reduce the effectiveness of anti-tumour immunity. Ultimately, the mathematical model presented in this paper may provide a framework to help biologists and clinicians to better understand the mechanisms that are responsible for the emergence of different outcomes of immunotherapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is classified as the third leading cancer globally and one of the major causes of morbidity and mortality around the world. The interaction of the immune system with the cancer cells plays a vital role in CRC progression. Regulatory T cells (Tregs) are a form of T cells, which regulate and suppress unwanted activation of the immune system and play a major role in preventing autoimmune diseases. Tregs exhibit a significant role in immune modulation during CRC progression through accumulation in the tumor microenvironment (TME) and suppression of immunity against tumor specific antigens promoting tumor progression. The role of Tregs in CRC progression and its interaction with other immune cells within CRC TME and current clinical trials were reviewed in this paper. [Display omitted] • Discusses the role of Tregs in immune modulation during CRC progression. • Explores the role of Tregs in CRC tumor microenvironment. • Highlights the mechanism of Tregs in CRC growth and metastasis. • Identifies and discusses current clinical trials targeting Tregs in CRC therapy. [ABSTRACT FROM AUTHOR]

Helicobacter pylori ( H. pylori ) infection is regarded as the major cause of various gastric diseases (gastritis, peptic ulcers and gastric cancer) and induces the production of several cytokines. Interleukin-17 (IL-17) is recently recognized as an important player in the pathophysiology of infectious and immune-mediated gastrointestinal diseases. H. pylori infection increases IL-17 in the gastric mucosa of humans. IL-17 usually causes secretion of IL-8 through activation of ERK 1/2 MAP kinase pathway. The released IL-8 attracts neutrophils promoting inflammation. T regulatory cells (Tregs) suppress the inflammatory reaction driven by IL-17, there by favoring bacterial persistence in H. pylori -infection. The pathogenesis of H. pylori -induced inflammation is not well understood. Inflammation is promoted by both host factors and H. pylori factors, such as the proteins cytotoxin associated gene A (cagA) and vacuolating cytotoxin A (vacA). IL-1β, IL-6, tumor necrosis factor (TNF)-α, TGF-β1, IL-17, IL-18, IL-21 and IL-22 have been reported to be involved in H. pylori -induced gastric mucosal inflammation, but the details and relation to different patterns of inflammation remain unclear. Numerous studies have demonstrated important functions of IL-17 in acute and chronic inflammatory processes. This paper reviews the role of IL-17 in gastritis, peptic ulcers and gastric cancer related to H. pylori . [ABSTRACT FROM AUTHOR]

Abstract: In this paper, we sought to identify the CD4+ T-cell dynamics in the course of HIV infection in response to continuous and intermittent intravenous courses of interleukin-2 (IL-2), the principal cytokine responsible for progression of CD4+ T-lymphocytes from the G1 to the S phase of the cell cycle. Based on multivariate regression models, previous literature has concluded that the increase in survival of CD4+ T-cell appears to be the critical mechanism leading to sustained CD4+ T-cell levels in HIV-infected patients receiving intermittent IL-2 therapy. Underscored by comprehensive mathematical modeling, a major finding of the present work is related to the fact that, rather than due to any increase in survival of CD4+ T-cells, the expressive, selective and sustained CD4+ T-cell expansions following IL-2 administration may be related to the role of IL-2 in modulating the dynamics of Fas-dependent apoptotic pathways, such as activation-induced cell death (AICD) or HIV-specific apoptotic routes triggered by viral proteins. [Copyright &y& Elsevier]

Abstract: For HIV patients, lifelong therapy is generally required to control their viral replication and it is very difficult to effectively eradicate HIV infection from the host. In this paper, using a mathematical model, we show that the stimulation of CD4+ T cells to proliferate in the presence of HIV is one possible factor causing such a difficulty. This is based on the fact that if the proliferation rate is non-negligible, then the model exhibits a backward bifurcation and hysteresis. Fitting to clinical data shows that the CD4+ T-cell proliferation does play an important role for HIV infection under antiretroviral therapy. The model and analysis are then extended to incorporate a bilinear term to account for the loss of free infectious virions during attacking the target cells. Our analysis suggests that, to effectively control HIV infection, antiretroviral therapies should aim at increasing the effectiveness of reverse transcriptase inhibitors and protease inhibitors, discouraging the stimulation of CD4+ T cells, and increasing the loss rate of virus particles when they infect the healthy CD4+ T cells. [Copyright &y& Elsevier]

Abstract: Epstein-Barr virus (EBV) can infect both B cells and epithelial cells. Infection of B cells enables the virus to persist within a host while infection of epithelial cells is suggested to amplify viral output. Data from a recent study have shown that the virus shedding in EBV positive individuals is relatively stable over short periods of time but varies significantly over long periods. The mechanisms underlying the regulation of virus shedding within a host are not fully understood. In this paper, we construct a model of ordinary differential equations to study the dynamics of virus shedding into the saliva of infected hosts. Infection of epithelial cells is further separated into infection by virus released from B cells and virus released from epithelial cells. We use the model to investigate whether the long-term variation and short-term stability of virus shedding can be generated by three possible factors: stochastic variations in the number of epithelial cells susceptible to virus released from infected B cells, to virus released from infected epithelial cells, or random variation in the probability that CD8+ T cells encounter and successfully kill infected cells. The results support all three factors to explain the long-term variation but only the first and third factors to explain the short-term stability of virus shedding into saliva. Our analysis also shows that clearance of virus shedding is possible only when there is no virus reactivation from B cells. [Copyright &y& Elsevier]

Abstract: In the present paper, we aimed to examine the novel effects of cerebroside D, a glycoceramide compound, on murine experimental colitis. Cerebroside D significantly reduced the weight loss, mortality rate and alleviated the macroscopic and microscopic appearances of colitis induced by dexran sulfate sodium. This compound also decreased the levels of TNF-α, IFN-γ and IL-1β in intestinal tissue of mice with experimental colitis in a concentration-dependent manner, accompanied with markedly increased serum level of IL-10. Cerebroside D inhibited proliferation and induced apoptosis of T cells activated by concanavalin A or anti-CD3 plus anti-CD28 antibodies. The compound did not show an effect on naive lymphocytes but prevented cells from entering S phase and G2/M phase during T cells activation. Moreover, the treatment of cerebroside D led to apoptosis of activated T cells with the cleavage of caspase 3, 9, 12 and PARP. These results showed multiple effects of cerebroside D against activated T cells for a novel approach to treatment of colonic inflammation. [Copyright &y& Elsevier]

Abstract: The strategies of structured treatment interruptions (STIs) of antiretroviral therapies have been proposed for clinical management of HIV infected patients, but clinical studies on STIs failed to achieve a consistent conclusion for this strategy. To evaluate the STI strategies, in particular, CD4+ T cell count-guided STIs, and explain these controversial conclusions from different clinical studies, in this paper we propose to use piecewise HIV virus dynamic models to quantitatively explore the STI strategies and investigate their dynamic behaviors. Our analysis results indicate that CD4+ T cell counts can be maintained above a safe level using the STI with a single threshold or a threshold window. Numerical simulations show that the CD4+ T cell counts either fluctuate or approach a stable level for a patient, depending on the prescribed upper or lower threshold values. In particular, the CD4+ T cell counts can be stabilized at a desired level if the threshold policy control is applied. The durations of drug-on and drug-off are very sensitive to the prescribed upper or lower threshold levels, which possibly explains why the on–off strategy with fixed schedule or an STI strategy with frequent switches are associated with the high rate of failure. Our findings suggest that it is critical to carefully choose the thresholds of CD4+ T cell count and individualize the STIs for each individual patient based on initial CD4+ T cell counts. [Copyright &y& Elsevier]

Abstract: Some self-reactive immature T cells escape negative selection in the thymus and may cause autoimmune diseases later. In the periphery, if T cells are stimulated insufficiently by peptide-major histocompatibility complex, they become inactive and their production of cytokines changes, a phenomenon called “T cell anergy”. In this paper, we explore the hypothesis that T cell anergy may function to reduce the risk of autoimmunity. The underlying logic is as follows: Since those self-reactive T cells that receive strong stimuli from self-antigens are eliminated in the thymus, T cells that receive strong stimuli in the periphery are likely to be non-self-reactive. As a consequence, when a T cell receives a weak stimulus, the likelihood that the cell is self-reactive is higher than in the case that it receives a strong stimulus. Therefore, inactivation of the T cell may reduce the danger of autoimmunity. We consider the formalism in which each T cell chooses its response depending on the strength of stimuli in order to reduce the risk of autoimmune diseases while maintaining its ability to attack non-self-antigens effectively. The optimal T cell responses to a weak and a strong stimulus are obtained both when the cells respond in a deterministic manner and when they respond in a probabilistic manner. We conclude that T cell anergy is the optimal response when a T cell meets with antigen-presenting cells many times in its lifetime, and when the product of the autoimmunity risk and the number of self-reactive T cells has an intermediate value. [Copyright &y& Elsevier]

Abstract: This paper shows that in vitro infection of human monocytes by Mycobacterium tuberculosis affected monocyte to macrophage differentiation. Despite the low bacterial load used, M. tuberculosis-infected monocytes had fewer granules, displayed a reduced number of cytoplasmic projections and decreased HLA class II, CD68, CD86 and CD36 expression compared to cells differentiated in the absence of mycobacteria. Infected cells produced less IL-12p70, TNF-α, IL-10, IL-6 and high IL-1β in response to lipopolysaccharide and purified protein M. tuberculosis-derived. Reduced T-cell proliferative response and IFN-γ secretion in response to phytohemagglutinin and culture filtrate proteins from M. tuberculosis was also observed in infected cells when compared to non-infected ones. The ability of monocytes differentiated in the presence of M. tuberculosis to control mycobacterial growth in response to IFN-γ stimulation was attenuated, as determined by bacterial plate count; however, they had a similar ability to uptake fluorescent M. tuberculosis and latex beads compared to non-infected cells. Recombinant IL-1β partially altered monocyte differentiation into macrophages; however, treating M. tuberculosis-infected monocytes with IL-1RA did not reverse the effects of infection during differentiation. The results indicated that M. tuberculosis infection altered monocyte differentiation into macrophages and affected their ability to respond to innate stimuli and activate T-cells. [Copyright &y& Elsevier]

Abstract: Oral lichen planus (OLP) is a chronic inflammatory disorder of oral mucosa, which represents cell-mediated autoimmune diseases. Pathological study demonstrated that abundant T lymphocytes infiltrated the oral mucosa, in which the activated T cells that trigger apoptosis of oral epithelial cells is an important mechanism for OLP. However, to date the molecular mechanisms underlying the T lymphocytes infiltration and accumulation in OLP remain unclear. In this paper, we found that the levels of plasma OPN were elevated and were associated with the up-regulated expressions of CD44 in OLP patients. In vitro, the addition of exogenous OPN can suppress the apoptosis of activated CD8+ T cells via CD44, and this T cell resistance to apoptosis may be attributed to the reduction of endogenous mature granzyme B. Our results suggested that the abnormally elevated levels of OPN may contribute to the abnormal infiltration and accumulation of the activated T cells by up-regulating CD44 in OLP. [Copyright &y& Elsevier]

Abstract: Metabolic bone diseases, such as rheumatoid arthritis (RA) and osteoporosis, affect hundreds and millions of people worldwide leading causes of long-term pain and disability. Effective clinical treatment for bone destruction in bone diseases is lacking because the knowledge about molecular mechanisms leading to bone destruction are incompletely understood. Recently, it has been confirmed that regulatory T cells (Tregs) play a crucial role in suppressing the immune response in the pathogenesis of various autoimmune diseases. In vitro, Tregs directly inhibit osteoclasts and differentiation and function. In mice, the injection of Tregs into the TNF transgenic results in enhanced systemic bone density. In addition, it has been shown that increase of Tregs numbers by overexpressing the FoxP3 is effective in the prevention of local and systemic bone destruction. In vivo treatment with anti-CD28 superagonist antibody leading to a stronger increase in Tregs numbers protect against TNF-a-induced bone loss in TNF-transgenic mice. In agreement, Tregs can control ovariectomy-induced bone loss in FoxP3-transgenic mice. In this paper, we will briefly discuss the biological features of Tregs and summarize recent advances on the role of Tregs in the pathogenesis and treatment of bone loss in metabolic bone diseases. [Copyright &y& Elsevier]

Abstract: The adaptive immune system of a vertebrate may attack its own body, causing autoimmune diseases. Regulatory T cells suppress the activity of the autoreactive effector T cells, but they also interrupt normal immune reactions against foreign antigens. In this paper, we discuss the optimal number of regulatory T cells that should be produced. We make the assumptions that some self-reactive immature T cells may fail to interact with their target antigens during the limited training period and later become effector T cells causing autoimmunity, and that regulatory T cells exist that recognize self-antigens. When a regulatory T cell is stimulated by its target self-antigen on an antigen-presenting cell (APC), it stays there and suppresses the activation of other naive T cells on the same APC. Analysis of the benefit and the harm of having regulatory T cells suggests that the optimal number of regulatory T cells depends on the number of self-antigens, the severity of the autoimmunity, the abundance of pathogenic foreign antigens, and the spatial distribution of self-antigens in the body. For multiple types of self-antigen, we discuss the optimal number of regulatory T cells when the self-antigens are localized in different parts of the body and when they are co-localized. We also examine the separate regulation of the abundances of regulatory T cells for different self-antigens, comparing it with the situation in which they are constrained to be equal. [Copyright &y& Elsevier]

Abstract: The immune system of vertebrates may attack its own body and cause autoimmunity diseases. To prevent autoimmunity, regulatory T cells suppress the activity of the autoreactive effector T cells, but they also interrupt normal immune reactions against foreign antigens. In this paper, we discuss the advantage of having some regulatory T cells by considering the host''s ability of coping with foreign antigens and the harm of autoimmunity. Assumptions are as follows: the immature T cells reactive to abundant self-antigens are eliminated, those reactive to rare self-antigen will become regulatory T cells, and those that fail to interact with the antigens to which they are reactive will become effector T cells. Some self-reactive immature T cells may fail to interact with their own target antigens during the limited training period, and will later become effector T cells, causing autoimmunity. Analysis suggests that, having some regulatory T cells can never be advantageous to the host, if activated regulatory T cells suppress effector T cells at any location of the body (global suppression). In contrast, producing some regulatory T cells can be beneficial, if the body is composed of many compartments and regulatory T cells suppress the immune reactions only within the same compartment (localized suppression). This requires regulatory T cells to stop circulating once they are activated by their own target self-antigens. [Copyright &y& Elsevier]

Abstract: Cytotoxic T lymphocytes (CTLs) play a dominant role in the pathogenesis of autoimmune diabetes, commonly denoted Type 1 Diabetes (T1D). These CTLs (notably T cells) recognize and kill insulin-secreting pancreatic cells, reducing their number by . The resulting reduction of insulin secretion causes the defective regulation of glucose metabolism, leading to the characteristic symptoms of diabetes. Recognition of cells as targets by CTLs depends on the interactions between MHC-peptide complexes on the surface of cells and receptors (TCRs) on T cells. Those CTLs with high affinity TCRs (also called high avidity T cells) cause most of the harm, while those with low affinity TCRs (also called low avidity T cells) play a more mysterious role. Recent experimental evidence suggests that low avidity T cells accumulate as memory T cells during the disease and may be protective in NOD mice (a strain prone to developing T1D), delaying disease progression. It has been hypothesized that such low avidity T cells afford disease protection either by crowding the islets of Langerhans, where cells reside, or by killing antigen presenting cells (APCs). In this paper, we explore the hypothesized mechanisms for this protective effect in the context of a series of models for (1) the interactions of low and high avidity T cells, (2) the effect of APCs and (3) the feedback from cell killing to autoantigen-induced T cell proliferation. We analyze properties of these models, noting consistency of predictions with observed behaviour. We then use the models to examine the influence of various treatment strategies on the progression of the disease. The model reveals that progressive accumulation of memory low avidity autoreactive T cells during disease progression makes treatments aimed at expanding these protective T cell types more effective close to, or at the onset of clinical disease. It also provides evidence for the hypothesis that low avidity T cells kill APCs (rather than the alternate hypothesis that they crowd the islets). [Copyright &y& Elsevier]

Abstract: Epstein–Barr virus (EBV) is an important human pathogen that establishes a life-long persistent infection and for which no precise animal model exists. In this paper, we describe in detail an agent-based model and computer simulation of EBV infection. Agents representing EBV and sets of B and T lymphocytes move and interact on a three-dimensional grid approximating Waldeyer''s ring, together with abstract compartments for lymph and blood. The simulation allows us to explore the development and resolution of virtual infections in a manner not possible in actual human experiments. Specifically, we identify parameters capable of inducing clearance, persistent infection, or death. [Copyright &y& Elsevier]

Abstract: Mathematical models of HIV therapy have traditionally amalgamated the action of antiretroviral drugs, trading the complexity of the situation in favour of simpler—and hence mathematically tractable—models. However, the effects of ignoring such dynamics remain underexamined. In this paper, the traditional method of dosing (where the dose is modelled implicitly as a proportional inhibition of viral infection and production) is compared to a model that accounts for drug dynamics via explicit compartments. Four limiting cases are examined: frequent dosing of both major classes of drugs, absence of either drug, frequent dosing of one drug alone, or frequent dosing of the other drug alone. When drugs are absent, both models predict that the virus will dominate and the uninfected T cell counts will be low. When reverse transcriptase inhibitors are given frequently, both models predict that the virus will be theoretically eliminated and the uninfected T cell counts will be high; this is true regardless of whether the reverse transcriptase inhibitors act alone or in conjunction with protease inhibitors. However, if protease inhibitors alone are given frequently, then the implicit model predicts that the virus will be eliminated and the uninfected T cell counts will be high, whereas the (more realistic) explicit model predicts that the reverse situation may occur. In the latter case, critically, protease-only regimens may ultimately result in the death of the patient. It follows that the impact of drug regimens consisting only of protease inhibitors must be urgently re-examined, if such outcomes have been based on overly simplistic modelling. [Copyright &y& Elsevier]

Abstract: In this paper, we focus our attention on the relevance of HLA-G in cancer in the light of our recent advances on the expression and immunological function of HLA-G. Regarding HLA-G function, we recently showed that in addition to its direct inhibitory effects on T, APC and NK function, HLA-G induces suppressor cells via two distinct processes: (i) either by cell differentiation of naïve T cells into lasting suppressor T cells or (ii) by rapid transfer of HLA-G from APC or tumor cells to T or NK cells converting them into temporary HLA-G-positive suppressor cells. Regarding HLA-G expression, we described that tumor-microenvironment factors such as hypoxia, IDO and, TNF-α regulate the expression of HLA-G by tumor cells in a way that favors tumor escape from NK lysis. These findings reinforce the role of HLA-G as one mechanism of tumor-driven immune evasion and provide potential targets for testing novel anticancer treatment strategies. [Copyright &y& Elsevier]

Abstract: Mathematical models of T cell population dynamics after infection typically assume that T cells differentiate according to a linear process in which they first become effector cells, and then after some time, differentiate further into memory cells. In this paper, we offer a different mathematical model which can equally well capture T cell dynamics, using data from lymphocytic choriomeningitis (LCMV) infection. Our model assumes that memory cells are intermediates that further differentiate into effector cells only from additional or stronger antigenic stimulation. Our assumption naturally leads to a testable prediction about the generation of T cell memory—that the memory phenotype of T cells should be present in detectable numbers during the expansion phase of the response. We use our model to estimate a rate of differentiation from memory type cells to effectors. We argue that this differentiation assumption, where memory cells are intermediates, captures recent experimental work on T cell differentiation, and hence this new mathematical model could be helpful in doing further studies of T cell population dynamics. We also propose a method of distinguishing the models by examining the ratio of memory T cells detectable long after an infection to the peak numbers of T cells at the end of the expansion phase. [Copyright &y& Elsevier]

Abstract: Several prevalent and life-threatening agents enter the organism via the mucosa. In this case, a mucosal cellular immune response is essential for protection and is therefore considered the main objective of vaccination. The frequency of antigen-specific CD4+ and CD8+ T cells can be determined directly in human whole blood by a combination of surface marker and intracellular cytokine staining. Immune cells primed in the mucosal compartment also migrate through the blood and can be identified by expression of the gut-specific homing receptor α4β7. Simultaneously, these lymphocytes can be functionally characterized regarding their differentiation status by analysis of CD45RO and CD27 expression and effector functions by measuring intracellular perforin or granzyme B content. Thus, the technique described in the paper is a powerful tool for clinical monitoring of the total cellular immune response to complex antigens during infection or vaccination. [Copyright &y& Elsevier]

Abstract: Antigen recognition by T cells is a key event in the adaptive immune response. T cells scan the surface of antigen-presenting cells (APCs) or target cells for specific peptides bound to MHC molecules. In the physiological setting, a typical APC presents tens of thousands of diverse endogenous self-derived peptides complexed to MHC (pMHC complexes). When ‘foreign’ peptides are presented, they constitute a small fraction of the total surface peptide repertoire. As T cells seem to be capable of discerning minute amounts of ‘foreign’ peptides among a complex background of self-peptides, endogenous peptides are generally assumed to play no role in recognition. However, recent results suggest that these background peptides may alter the sensitivity of T cells to foreign peptides. Current experimental limitations preclude analysis of peptide mixtures approaching physiological complexity, making it difficult to further address the role of complex background peptides. In this paper, we present a computational model to test how complex, varied peptide populations on an APC could potentially modulate a T cell''s ability to detect the presence of small numbers of agonist peptides among a diverse population. We use the model to investigate the notion that under physiological conditions, T cell recognition of foreign peptides is context dependent, that is, T cells process signals gathered from all pMHC interactions, not just from a few agonist peptides while ignoring all others. [Copyright &y& Elsevier]

Abstract: Despite the fact that the negative regulatory element (NRE) within the upstream regulatory region of human IL-2 receptor α (IL-2Rα) gene has been identified two decades ago, mechanisms of the NRE function on the gene are hitherto unknown. In this paper, we report for the first time that the immunoglobulin transcription factor 2B (ITF2B) encoded by transcription factor 4 (TCF4) gene is a NRE binding protein. The full-length TCF4 cDNA clone was obtained from a HTLV-1 transformed human peripheral T cell MACHERMAKER cDNA library with NRE as the bait in yeast one-hybrid system. The NRE binding ability of ITF2B was further confirmed in chromatin-immunoprecipitation assay. Competitive RT-PCR-based promoter activity assay showed that over-expression of ITF2B protein inhibited the expression of IL-2Rα gene in Jurkat cells in an NRE-dependent manner. The function of ITF2B on the inhibition of both the IL-2Rα and the 5′LTR activity of HIV-1 shed light on the essence of NRE binding protein as a potential target for immune therapy and treatment in AIDS patients. [Copyright &y& Elsevier]

Abstract: Besides pathology endpoints, additional immune function endpoints have been included in the Note for Guidance on Repeated Dose Toxicity by the European Union (July 2001), which concern the analysis of antibody responses to a T-cell-dependent antigen. Guidance papers of other regulatory authorities are published as well. The main issue is the need for functional immunotoxicity testing to detect unintended immunosuppression. The International Conference on Harmonization (ICH) has surveyed studies from the files of the pharmaceutical industry to find the proportion of compounds that can be detected by additional immunotoxicity testing. Preliminary analysis shows that 10–15% of the compounds in the survey only react positively to the additional tests. More data are requested from the pharmaceutical industry. The Expert Working Group of the ICH has decided to choose a cause-for-concern approach to immmunotoxicity rather than a routine-screening approach. The causes for concern are to be defined during ICH negotiations. [Copyright &y& Elsevier]

Abstract: Signaling pathways such as the pre-TCR and Wnt pathways regulate α/β T cell differentiation in thymus. Mice lacking an essential component of the pre-TCR exhibit arrest at the (CD4−CD8−) (CD44−CD25+) stage (DN3) of thymocyte development, and introduction of p53 deficiency into those mice abrogates this arrest, resulting in transition to the (CD4+CD8+) double-positive (DP) stage. This paper examines the effect of inactivation of p53 on thymocyte development in Bcl11b−/− mice that exhibit arrest at the DN3 or (CD4−CD8+) immature single-positive (ISP) stage. No DP thymocytes were detected in thymocytes of adoptive transfer experiments in scid mice that were derived from p53−/−Bcl11b−/− precursors but ISP thymocytes increased in the proportion and in the cell number approximately three times higher than those from Bcl11b−/− precursors. Consistently, the level of apoptosis decreased to the level of wild-type precursors. These results suggest that inactivation of p53 is sufficient for DN3 thymocytes to differentiate into the ISP, but not to DP, stage of thymocyte development in Bcl11b−/− mice. This provides evidence for a novel p53-mediated checkpoint that regulates the transition from the DN3 to ISP stage of thymocyte development. [Copyright &y& Elsevier]

Abstract: Antigen recognition by cytotoxic CD8 T cells is dependent upon a number of critical steps in MHC class I antigen processing including proteosomal cleavage, TAP transport into the endoplasmic reticulum, and MHC class I binding. Based on extensive experimental data relating to each of these steps there is now the capacity to model individual antigen processing steps with a high degree of accuracy. This paper demonstrates the potential to bring together models of individual antigen processing steps, for example proteosome cleavage, TAP transport, and MHC binding, to build highly informative models of functional pathways. In particular, we demonstrate how an artificial neural network model of TAP transport was used to mine a HLA-binding database so as to identify HLA-binding peptides transported by TAP. This integrated model of antigen processing provided the unique insight that HLA class I alleles apparently constitute two separate classes: those that are TAP-efficient for peptide loading (HLA-B27, -A3, and -A24) and those that are TAP-inefficient (HLA-A2, -B7, and -B8). Hence, using this integrated model we were able to generate novel hypotheses regarding antigen processing, and these hypotheses are now capable of being tested experimentally. This model confirms the feasibility of constructing a virtual immune system, whereby each additional step in antigen processing is incorporated into a single modular model. Accurate models of antigen processing have implications for the study of basic immunology as well as for the design of peptide-based vaccines and other immunotherapies. [Copyright &y& Elsevier]

Abstract: Both Fas and Fas ligand (FasL) are expressed in the thymus. Although reports suggest that they are important throughout the thymocyte maturation process their precise role remains elusive. The present paper characterizes the expression of FasL in the thymus and in the TEA3A1 and BT1B functional thymic epithelial cell (TEC) lines. FasL expression by thymus fractions, TEA3A1, and BT1B cells was detected by Northern blot analysis. In TEA3A1 cells, we discovered that FasL protein expression was localized to caveolae membrane domains. This restricted subcellular localization of FasL, together with reports describing the localization of the major histocompatibility complex proteins, the T cell receptor and Fas to caveolae membrane domains, may provide a mechanism for the deletion of thymocytes during negative selection. Finally, using semi-quantitative RT-PCR we found that FasL expression by TECs is regulated by glucocorticoids. [Copyright &y& Elsevier]

In this paper, we propose and analyse a mathematical model for chronic myelogenous leukemia (CML), a cancer of the blood. We model the interaction between naive T cells, effector T cells, and CML cancer cells in the body, using a system of ordinary differential equations which gives rates of change of the three cell populations. One of the difficulties in modeling CML is the scarcity of experimental data which can be used to estimate parameters values. To compensate for the resulting uncertainties, we use Latin hypercube sampling (LHS) on large ranges of possible parameter values in our analysis. A major goal of this work is the determination of parameters which play a critical role in remission or clearance of the cancer in the model. Our analysis examines 12 parameters, and identifies two of these, the growth and death rates of CML, as critical to the outcome of the system. Our results indicate that the most promising research avenues for treatments of CML should be those that affect these two significant parameters (CML growth and death rates), while altering the other parameters should have little effect on the outcome. [Copyright &y& Elsevier]

Fratricide between CD8+ T lymphocytes is known to occur in HTLV-I and possibly HSV-1 and HIV-1 infection. However it is not known what effect, if any, T-cell fratricide has on the course of infection. Here we present simple mathematical techniques to investigate T-cell fratricide with particular reference to HTLV-I infection. Using a general model we predict the qualitative and quantitative effect of fratricide on HTLV-I equilibrium proviral load. We also investigate the effect of fratricide on the probability of viral clearance.We show that, surprisingly, fratricide can lead either to an increase or a decrease in equilibrium proviral load. We derive the conditions necessary for fratricide to cause a decrease in load and deduce that, for the five HTLV-I-positive patients considered here, fratricide has probably caused an increase in equilibrium load. We also estimate the percentage increase in load that is attributable to fratricide and determine the parameters that should be measured in order to improve this estimate. Finally, we show that fratricide reduces the probability of viral clearance.Mathematical modelling of HTLV-I infection, as is often the case in biology, is severely hampered by a lack of experimental data. Consequently it is difficult to know what functional form a model should take. The behaviour of complex nonlinear systems is highly model-dependent. Predictions based on theoretical models are therefore sensitive to the choice of model; this is a very severe problem that undermines and limits the success of the application of mathematics to immunology. In this paper we reduce the model dependency of the results in two ways—by considering (analytically) a general model with a minimal number of assumptions and, where this is not possible, by checking (numerically) that a wide range of models yield the same results. We therefore begin to develop two practical methods for dealing with the problem of robustness in mathematical models of the immune system. [Copyright &y& Elsevier]

Recent experimental results show that even brief stimulation with antigen can cause antigen-specific CD8 T-cells to undergo sustained proliferation followed by differentiation into memory cells. These results show that the dynamics of these immune responses are not governed by constant monitoring of antigen levels, but rather that following stimulation immune cells commit to a “program”. At present relatively little is known about the program which governs CD8 cell proliferation and differentiation. For example, we do not know whether the program is completely specified by the initial encounter of a T cell with antigen, or whether it subsequently can be modified by the amount of antigen present. Nor do we know whether the entire program for T cell proliferation and differentiation resides within the T cell itself, or whether some component(s) of the program are determined by cells or molecules external to the CD8 cell. In this paper we construct simple mathematical models which incorporate antigen-independent proliferation and differentiation of CD8 cells during acute infections. We use these models to determine what characteristics the program must have in order to be consistent with the existing data on the dynamics of CD8 responses, and in particular to answer the questions posed above. Our results suggest that the program is not completely defined by the initial encounter of T cell with antigen but may be augmented by exposure to antigen in a brief window shortly after infection; furthermore, parts of the program may reside external to the T-cells. Finally we examine some of the consequences of the “program” for pathogen–host coevolution. [Copyright &y& Elsevier]

The protein-tyrosine kinase p56lck is the product of the lck gene. It plays a pivotal role in T-lymphocyte activation and thymocyte development, as indicated by the defective immune responses of lck−/− mice. We have demonstrated that an exon 7-deleted lck mRNA is produced by alternative splicing in all human cells expressing the lck gene. We have now looked for the protein encoded by this spliced lck mRNA and attempted to determine the function of the deleted Lck protein. This paper shows that the LckΔ7 protein is present in JCaM1.6 T-cells and we inferred that this isoform accounts for 15% of the total Lck proteins in the parental Jurkat T-cell line. We report that deletion of the first 51 amino-acids (exon 7) of the Lck catalytic domain greatly reduces the kinase activity of the recombinant protein. The residual activity can, nevertheless, be enhanced by adding Mn2+, whereas this cation has no effect on the activity of the p56lck mutated in its active site (K273E). The enforced production of LckΔ7 protein in transfected Jurkat cells results in slower cell proliferation than does p56lck. These findings suggest that the LckΔ7 protein is a p56lck cell-signaling regulator. This mechanism could be common to both humans and mice, in which we also found the exon 7-spliced lck transcript. [Copyright &y& Elsevier]

• A mathematical model for combination therapy using engineered T cells and IL-2. • The results provide a TCR T cell dose window for a successful therapy. • Combination therapy does not always provide a better outcome. Adoptive T cell based immunotherapy is gaining significant traction in cancer treatment. Despite its limited efficacy so far in treating solid tumors compared to hematologic cancers, recent advances in T cell engineering render this treatment increasingly more successful in solid tumors, demonstrating its broader therapeutic potential. In this paper we develop a mathematical model to study the efficacy of engineered T cell receptor (TCR) T cell therapy targeting the E7 antigen in cervical cancer cell lines. We consider a dynamical system that follows the population of cancer cells, TCR T cells, and IL-2 treatment concentration. We demonstrate that there exists a TCR T cell dosage window for a successful cancer elimination that can be expressed in terms of the initial tumor size. We obtain the TCR T cell dose for two cervical cancer cell lines: 4050 and CaSki. Finally, a combination therapy of TCR T cell and IL-2 treatment is studied. We show that certain treatment protocols can improve therapy responses in the 4050 cell line, but not in the CaSki cell line. [ABSTRACT FROM AUTHOR]

• Platelet specific CD4+ T cells are required for anti-platelet antibody production. • Th1/Th2 immune deviation is directly implicated in ITP development and progression. • Th17 cells and platelets have multifaceted and pro-active mutual relationship. • Both numerical and functional abnormalities of Tregs were observed in ITP patients. • Th22, Th9 and Tfh cells could be also associated with ITP pathophysiology. Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts due to enhanced platelet clearance and compromised production. Traditionally, ITP was regarded a B cell mediated disorder as anti-platelet antibodies are detected in most patients. The very nature of self-antigens, evident processes of isotype switching and the affinity maturation of anti-platelet antibodies indicate that B cells in order to mount anti-platelet immune response require assistance of auto-reactive CD4+ T cells. For a long time, ITP pathogenesis has been exclusively reviewed through the prism of the disturbed balance between Th1 and Th2 subsets of CD4+ T cells, however, more recently new subsets of these cells have been described including Th17, Th9, Th22, T follicular helper and regulatory T cells. In this paper, we review the current understanding of the role and immunological mechanisms by which CD4+ T cells contribute to the pathogenesis of ITP. [ABSTRACT FROM AUTHOR]

• Two IL-2 paralogs (IL-2 and IL-2L) have been identified in sea bass. • IL-2 and IL-2L synteny and gene organization has been analyzed. • The molecular structure and expression analysis of these two paralogs has been studied. • The bioactivity of the sea bass IL-2 paralogs has been explored. • IL-2 and IL-2L are involved in fish T cell development and show a distinct biological role. In mammals, interleukin (IL)-2, initially known as a T-cell grow factor, is an immunomodulatory cytokine involved in the proliferation of T cells upon antigen activation. In bony fish, some IL-2 orthologs have been identified, but, recently, an additional IL-2like (IL-2L) gene has been found. In this paper, we report the presence of these two divergent IL-2 isoforms in sea bass (Dicentrarchus labrax L.). Genomic analyses revealed that they originated from a gene duplication event, as happened in most percomorphs. These two IL-2 paralogs show differences in the amino acid sequence and in the exon 4 size, and these features could be an indication that they bind preferentially to different specific IL-2 receptors. Sea bass IL-2 paralogs are highly expressed in gut and spleen, which are tissues and organs involved in fish T cell immune functions, and the two cytokines could be up-regulated by both PHA stimulation and vaccination with a bacterial vaccine, with IL-2L being more inducible. To investigate the functional activities of sea bass IL-2 and IL-2L we produced the corresponding recombinant molecules in E. coli and used them to in vitro stimulate HK and spleen leukocytes. IL-2L is able to up-regulate the expression of markers related to different T cell subsets (Th1, Th2 and Th17) and to Treg cells in HK, whereas it has little effect in spleen. IL-2 is not active on these markers in HK, but shows an effect on Th1 markers in spleen. Finally, the stimulation with recombinant IL-2 and IL-2L is also able to induce in vitro proliferation of HK- and spleen-derived leukocytes. In conclusion, we have demonstrated that sea bass possess two IL-2 paralogs that likely have an important role in regulating T cell development in this species and that show distinct bioactivities. [ABSTRACT FROM AUTHOR]