The Experts below are selected from a list of 40437 Experts worldwide ranked by ideXlab platform
De Lisa Fairweather - One of the best experts on this subject based on the ideXlab platform.
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cutting edge cross regulation by tlr4 and t cell ig Mucin 3 determines sex differences in inflammatory heart disease
Journal of Immunology, 2007Co-Authors: Sylvia Frisanchokiss, Jennifer F Nyland, Sarah E Davis, Masheka A Barrett, Daniela Cihakova, Noel R Rose, Augusto J Frisancho, De Lisa FairweatherAbstract:Recent clinical studies have reinforced the importance of sex-related differences in the pathogenesis of cardiovascular diseases, with an increased incidence and mortality in men. Similar to humans, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe inflammation in the heart even though viral replication is no greater than in females. We show that TLR4 and IFN-gamma levels are significantly elevated and regulatory T cell (Treg) populations significantly reduced in the heart of males following CVB3 infection, whereas females have significantly increased T cell Ig Mucin (Tim)-3, IL-4 and Treg. Blocking Tim-3 in males significantly increases inflammation and TLR4 expression while reducing Treg. In contrast, defective TLR4 signaling significantly reduces inflammation while increasing Tim-3 expression. Cross-regulation of TLR4 and Tim-3 occurs during the innate and adaptive immune response. This novel mechanism may help explain why inflammatory heart disease is more severe in males.
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cutting edge t cell ig Mucin 3 reduces inflammatory heart disease by increasing ctla 4 during innate immunity
Journal of Immunology, 2006Co-Authors: Sylvia Frisanchokiss, Jennifer F Nyland, Sarah E Davis, Masheka A Barrett, Shannon J L Gatewood, Dolores B Njoku, Daniela Cihakova, Ellen K Silbergeld, Noel R Rose, De Lisa FairweatherAbstract:Autoimmune diseases can be reduced or even prevented if proinflammatory immune responses are appropriately down-regulated. Receptors (such as CTLA-4), cytokines (such as TGF-beta), and specialized cells (such as CD4+CD25+ T regulatory cells) work together to keep immune responses in check. T cell Ig Mucin (Tim) family proteins are key regulators of inflammation, providing an inhibitory signal that dampens proinflammatory responses and thereby reducing autoimmune and allergic responses. We show in this study that reducing Tim-3 signaling during the innate immune response to viral infection in BALB/c mice reduces CD80 costimulatory molecule expression on mast cells and macrophages and reduces innate CTLA-4 levels in CD4+ T cells, resulting in decreased T regulatory cell populations and increased inflammatory heart disease. These results indicate that regulation of inflammation in the heart begins during innate immunity and that Tim-3 signaling on cells of the innate immune system critically influences regulation of the adaptive immune response.
Yannick Jacques - One of the best experts on this subject based on the ideXlab platform.
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il 15 trans signaling with the superagonist rli promotes effector memory cd8 t cell responses and enhances antitumor activity of pd 1 antagonists
Journal of Immunology, 2016Co-Authors: Melanie Desbois, Géraldine Teppaz, Clelia Coutzac, Elie Marcheteau, Coralie Beal, Magali Terme, Alain Gey, Sebastien Morisseau, Lisa Boselli, Yannick JacquesAbstract:Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Rα frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor-linker-IL-15 (RLI), designed to bypass the need of endogenous IL-15Rα. RLI consists of human IL-15 covalently linked to the human IL-15Rα sushi(+) domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)(high) T cell Ig Mucin-3(+) CD8(+) T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8(+) T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8(+) T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor-infiltrated lymphocyte reactivation with the combination anti-PD-1/RLI compared with 43 and 6% with RLI or anti-PD-1, respectively. Altogether, this work provides evidence that the sushi-IL-15Rα/IL-15 fusion protein RLI enhances antitumor activity of anti-PD-1 treatment and is a promising approach to stimulate host immunity.
Songcun Wang - One of the best experts on this subject based on the ideXlab platform.
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altered frequency and function of spleen ctla 4 tim 3 t cells are associated with miscarriage
Biology of Reproduction, 2019Co-Authors: Songcun Wang, Fengrun Sun, Chunqin Chen, Jinfeng QianAbstract:Normal pregnancy is associated with several immune adaptations in both systemic and local maternal-fetal interface to allow the growth of semi-allogeneic conceptus. A failure in maternal immune tolerance to the fetus may result in abnormal pregnancies, such as recurrent spontaneous abortion (RSA). The regulation of T cell homeostasis during pregnancy has important implications for maternal tolerance and immunity. Cytotoxic T-lymphocyte antigen-4(CTLA-4) and T-cell immunoglobulin Mucin-3 (Tim-3) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here we described the lower frequency of splenic T cells co-expressing CTLA-4 and Tim-3 accompanied by higher levels of pro-inflammatory but lower anti-inflammatory cytokines production in abortion-prone mouse model. Blockade CTLA-4 and Tim-3 pathways leaded to the dysfunction of splenic T cells. By the higher expression during normal pregnancy, CTLA-4 and Tim-3 co-expression on splenic T cells linked to immunosuppressive phenotype. As the spleen is an important site for peripheral immune activation, our data suggest potential non-invasive biomarkers and therapeutic targets for miscarriage.
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Blockade of CTLA-4 and Tim-3 pathways induces fetal loss with altered cytokine profiles by decidual CD4+T cells
Nature Publishing Group, 2019Co-Authors: Songcun Wang, Xingxing Zang, Chunqin Chen, Jinfeng Qian, Fengyun Sun, Mingyan Wang, Rui ZhuAbstract:Abstract The single and/or combination use of immune checkpoint blockade therapies in human infectious diseases and cancer are rapidly expanding. Despite early efforts, substantial uncertainty remains about the safety and efficacy of immune checkpoint blockade in some populations. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and T-cell immunoglobulin Mucin-3 (Tim-3) are the major targetable co-inhibitory receptors on T cells. Here we showed that in animal studies, treatment with either CTLA-4- or Tim-3-blocking antibody caused greater susceptibility to fetal loss with altered cytokine profiles by decidual CD4+T (dCD4+T) cells. CTLA-4 and Tim-3 pathways appeared to play key roles in maintaining maternal-fetal tolerance by regulating the function of dCD4+T cells. In addition, the abnormality in number and functionality of dCTLA-4+Tim-3+CD4+T cells was associated with miscarriage. These findings underscored the important roles of the CTLA-4 and Tim-3 pathways in regulating dCD4+T cells function and maintaining normal pregnancy. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care
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programmed cell death 1 pd 1 and t cell immunoglobulin Mucin 3 tim 3 regulate cd4 t cells to induce type 2 helper t cell th2 bias at the maternal fetal interface
Human Reproduction, 2016Co-Authors: Songcun Wang, Xiaoyong Zhu, Di Zhang, Yu Tao, Hailan PiaoAbstract:Study question Are the immune regulatory molecules programmed cell death-1 (PD-1) and T-cell immunoglobulin Mucin-3 (Tim-3) involved in regulating CD4+ T cell function during pregnancy? Summary answer PD-1 and Tim-3 promote Type 2 helper T cell (Th2) bias and pregnancy maintenance by regulating CD4+ T cell function at the maternal-fetal interface. What is known already The maternal CD4+ T cell response to fetal antigens is thought to be an important component of maternal-fetal tolerance during pregnancy. PD-1 and Tim-3 are important for limiting immunopathology. The co-expression of PD-1 and Tim-3 on T cells identifies a T cell subset with impaired proliferation and cytokine production. Combined blockade of Tim-3 and PD-1 could restore T cell function to the greatest degree. Study design, size, duration The expression of PD-1 and Tim-3 on CD4+ T cells was analyzed by flow cytometry, and in vitro and in vivo analyses were used to investigate the role of PD-1/Tim-3 signal in the regulation of CD4+ T cells function and pregnancy outcome. Participants/ materials, setting, methods A total of 88 normal pregnant women, 37 women with recurrent spontaneous abortion, 36 normal pregnant mice and 45 abortion-prone mice were included. We measure the expression of PD-1 and Tim-3 on CD4+ T cells and their relationship to the function of CD4+ T cells and pregnancy outcome, as well as the effects of blocking PD-1 and Tim-3 pathways on decidual CD4+ T (dCD4+ T) cells during early pregnancy. Main results and the role of chance PD-1 and Tim-3, by virtue of their up-regulation on dCD4+ T cells during pregnancy, define a specific effector/memory subset of CD4+ T cells and promote Th2 bias at the maternal-fetal interface. Using in vitro and in vivo experiments, we also found that combined targeting of PD-1 and Tim-3 pathways results in decreased production of Th2-type cytokines by dCD4+ T cells and increased fetal resorption of normal pregnant murine models. Moreover, decreased PD-1 and Tim-3 on dCD4+ T cells may be associated with miscarriage. Limitations and limits of caution Further study is required to examine the mechanism of PD-1 and Tim-3 effects on Th2 cytokine production by CD4+ T cells during pregnancy. Wider implications of the findings These results have important implications for understanding the physiological mechanisms that promote maternal-fetal tolerance. Our study also indicates that targeting Tim-3 and PD-1 pathways may represent novel therapeutic strategies to prevent pregnancy loss. Study funding/competing interests This study was supported by the National Basic Research Program of China (2015CB943300); National Nature Science Foundation of China (81490744, 91542116, 31570920, 81070537, 31171437, 81370770, 31270969, 31570920, 91542116); the Key Project of Shanghai Municipal Education Commission (14ZZ013) and the Key Project of Shanghai Basic Research from Shanghai Municipal Science and Technology Commission (12JC1401600). None of the authors have any conflict of interest to declare.
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pd 1 and tim 3 pathways are associated with regulatory cd8 t cell function in decidua and maintenance of normal pregnancy
Cell Death and Disease, 2015Co-Authors: Songcun Wang, Di Zhang, Yu Tao, Hailan Piao, X W Hong, Yuyan Wang, M M YuanAbstract:CD8+ T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin Mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8+ T-cell function and maintaining normal pregnancy.
Jerzy W Kupiecweglinski - One of the best experts on this subject based on the ideXlab platform.
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recipient t cell tim 3 and hepatocyte galectin 9 signalling protects mouse liver transplants against ischemia reperfusion injury
Journal of Hepatology, 2015Co-Authors: Ronald W Busuttil, Yuanxing Liu, Yu Zhang, Xiuda Shen, Feng Gao, Vijay K Kuchroo, Jerzy W KupiecweglinskiAbstract:Background & Aims By binding to T cell immunoglobulin Mucin-3 (TIM-3) on activated Th1 cells, galectin-9 (Gal-9) negatively regulates Th1-type alloimmunity. Although T cells contribute to hepatic ischemia-reperfusion injury (IRI), it is unknown whether negative T cell-dependent TIM-3 co-stimulation may rescue IR-stressed orthotopic liver transplants from innate immunity-driven inflammation. Methods We used wild type (WT) and TIM-3 transgenic (Tg) mice (C57BL/6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20h at 4°C in UW solution) and syngeneic orthotopic liver transplantation (OLT). Results Orthotopic liver transplants in WT or TIM-3Tg→TIM-3Tg groups were resistant against IR-stress, evidenced by preserved hepatocellular function (serum ALT levels) and liver architecture (Suzuki's score). In contrast, orthotopic liver transplants in WT or TIM-3Tg→WT groups were susceptible to IRI. TIM-3 induction in circulating CD4 + T cells of the recipient: (1) depressed T-bet/IFN-γ, while amplifying GATA3 and IL-4/IL-10 expression in orthotopic liver transplants; (2) promoted T cell exhaustion (PD-1, LAG-3) phenotype; and (3) depressed neutrophil and macrophage infiltration/function in orthotopic liver transplants. In parallel studies, we documented for the first time that Gal-9, a natural TIM-3 ligand, was produced primarily by and released from IR-stressed hepatocytes, both in vivo and in vitro . Moreover, exogenous recombinant Gal-9 (rGal-9) potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4 + T cells. Conclusions Harnessing TIM-3/Gal-9 signalling at the T cell–hepatocyte interface facilitates homeostasis in IR-stressed orthotopic liver transplants. Enhancing anti-oxidant hepatocyte Gal-9 potentiates liver IR-resistance. Negative regulation by recipient TIM-3 + CD4 + cells provides evidence for cytoprotective functions of a discrete T cell subset, which should be spared when applying T cell-targeted immunosuppression in transplant recipients.
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t cell immunoglobulin Mucin 3 determines severity of liver ischemia reperfusion injury in mice in a tlr4 dependent manner
Gastroenterology, 2010Co-Authors: Yoichiro Uchida, Hideo Yagita, Maria Cecilia S Freitas, Hisaya Akiba, Ronald W Busuttil, Nader Najafian, Jerzy W KupiecweglinskiAbstract:Background & Aims T-cell immunoglobulin Mucin ( TIM ) genes are expressed by T cells and regulate host immunity and tolerance. CD4 + T cells mediate innate immunity-dominated liver ischemia-reperfusion injury (IRI) by unknown mechanisms. TIM-1 is involved in liver IRI, which is activated in part by the Toll-like receptor (TLR)4; we investigated the role of TIM-3 and TLR4 in IRI. Methods Using an antibody against TIM-3 (anti–TIM-3), we studied TIM-3 signaling in mice following partial warm liver ischemia and reperfusion. Results Mice given anti–TIM-3 had more liver damage than controls. Histological studies revealed that anti–TIM-3 increased hepatocellular damage and local neutrophil infiltration, facilitated local accumulation of T cells and macrophages, and promoted liver cell apoptosis. Intrahepatic neutrophil activity; induction of proinflammatory cytokines and chemokines; and expression of cleaved caspase-3, nuclear factor-κB, and TLR4 all increased in mice given anti–TIM-3. Administration of anti–TIM-3 followed by anti–galectin-9 (Gal-9 is a TIM-3 ligand) increased production of interferon-γ by concanavalin A (ConA)-stimulated spleen T cells and expression of tumor necrosis factor-α and interleukin-6 in ConA-stimulated macrophages co-cultured with T cells. Anti–TIM-3 did not affect liver IRI in TLR4-deficient mice. Conclusion TIM-3 blockade exacerbated local inflammation and liver damage, indicating the importance of TIM-3–Gal-9 signaling in maintaining hepatic homeostasis. TIM-3–TLR4 cross-regulation determined the severity of liver IRI in TLR4-dependent manner; these findings provide important information about the modulation of innate vs adaptive responses in patients that received liver transplants. Negative co-stimulation signaling by hepatic T-cells might be developed to minimize innate immunity-mediated liver tissue damage.
Sylvia Frisanchokiss - One of the best experts on this subject based on the ideXlab platform.
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cutting edge cross regulation by tlr4 and t cell ig Mucin 3 determines sex differences in inflammatory heart disease
Journal of Immunology, 2007Co-Authors: Sylvia Frisanchokiss, Jennifer F Nyland, Sarah E Davis, Masheka A Barrett, Daniela Cihakova, Noel R Rose, Augusto J Frisancho, De Lisa FairweatherAbstract:Recent clinical studies have reinforced the importance of sex-related differences in the pathogenesis of cardiovascular diseases, with an increased incidence and mortality in men. Similar to humans, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe inflammation in the heart even though viral replication is no greater than in females. We show that TLR4 and IFN-gamma levels are significantly elevated and regulatory T cell (Treg) populations significantly reduced in the heart of males following CVB3 infection, whereas females have significantly increased T cell Ig Mucin (Tim)-3, IL-4 and Treg. Blocking Tim-3 in males significantly increases inflammation and TLR4 expression while reducing Treg. In contrast, defective TLR4 signaling significantly reduces inflammation while increasing Tim-3 expression. Cross-regulation of TLR4 and Tim-3 occurs during the innate and adaptive immune response. This novel mechanism may help explain why inflammatory heart disease is more severe in males.
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cutting edge t cell ig Mucin 3 reduces inflammatory heart disease by increasing ctla 4 during innate immunity
Journal of Immunology, 2006Co-Authors: Sylvia Frisanchokiss, Jennifer F Nyland, Sarah E Davis, Masheka A Barrett, Shannon J L Gatewood, Dolores B Njoku, Daniela Cihakova, Ellen K Silbergeld, Noel R Rose, De Lisa FairweatherAbstract:Autoimmune diseases can be reduced or even prevented if proinflammatory immune responses are appropriately down-regulated. Receptors (such as CTLA-4), cytokines (such as TGF-beta), and specialized cells (such as CD4+CD25+ T regulatory cells) work together to keep immune responses in check. T cell Ig Mucin (Tim) family proteins are key regulators of inflammation, providing an inhibitory signal that dampens proinflammatory responses and thereby reducing autoimmune and allergic responses. We show in this study that reducing Tim-3 signaling during the innate immune response to viral infection in BALB/c mice reduces CD80 costimulatory molecule expression on mast cells and macrophages and reduces innate CTLA-4 levels in CD4+ T cells, resulting in decreased T regulatory cell populations and increased inflammatory heart disease. These results indicate that regulation of inflammation in the heart begins during innate immunity and that Tim-3 signaling on cells of the innate immune system critically influences regulation of the adaptive immune response.