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Role of TIM Molecules in Regulatory and Inflammatory B cells in Allo andAutoimmunity

TIM 分子在同种异体和自身免疫中调节性和炎症性 B 细胞中的作用

基本信息

批准号：
10214475
负责人：
DAVID M ROTHSTEIN
金额：
$ 187.07万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214475
关键词：
Acute Address Adoptive Transfer Allograft Tolerance Allografting Anti-Inflammatory Agents Antibodies Antigen Presentation Autoantibodies Autoimmune Autoimmune Diabetes Autoimmune Diseases Autoimmunity B-Lymphocyte Subsets B-Lymphocytes Biology Cells Cellular Immunity Chronic Clinical Cues Data Development Exhibits Experimental Autoimmune Encephalomyelitis Genes Genetic Transcription Graft Rejection Heart Transplantation Host Defense Human Humoral Immunities Immune response Immunoglobulin G Inbred MRL lpr Mice Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interferon Type II Interleukin-10 Interleukin-17 Interleukin-6 Kidney Transplantation Ligation Link Location Lupus Mediating Modeling Mus Outcome Pathogenicity Patients Phenotype Play Population Production Regulation Role Shapes Signal Transduction Surface T cell response T-Lymphocyte Testing Time Transplant Recipients Transplantation Transplantation Tolerance Vascular Diseases allograft rejection anti-CD20 autoimmune arthritis autoimmune inflammation base biomarker identification clinically relevant cytokine falls immunoregulation improved insight isoimmunity kidney allograft loss of function member mutant novel pathogenic microbe phenotypic biomarker prevent progenitor programs response transcription factor transcriptome

项目摘要

In addition to humoral immunity, B cells play an important role shaping T effector responses through antigen presentation, costimulation, and cytokine production. Thus, B cell depletion ameliorates autoimmune diabetes and arthritis in mice, and rapidly improves RA and MS in humans, and outcomes do not correlate with fall in autoantibodies. In contrast, in both humans and mice, B cell depletion can also worsen autoimmunity, and can promote acute rejection and chronic vasculopathy in renal and cardiac transplant patients, respectively. These studies indicate that B cells can either enhance, or inhibit, inflammatory responses. In this regard, transfer of various B cell subsets can inhibit autoimmunity and allograft rejection through IL-10, and a growing list of other mechanisms. However, lack of a universal phenotype or master transcription factor (TF) for these Bregs has stymied the field. It is unknown whether these disparate cells are distinct or inter-related, or what regulates their differentiation or cytokine expression. Our preliminary data show that: 1) TIM-1 is an inclusive marker for IL-10+ Bregs. 2) Intact TIM-1 signaling on B cells regulates the expression of both TFs and various regulatory molecules (“regulatory module”). This allows us to test their role in Breg differentiation and function. 3) We also show that CpG-activated Pro-B cells transfer exceeding potent suppression, mediated by mature Breg progeny exhibiting different mechanisms of action in different locations. Both progenitors and progeny are TIM-1+, which allows us to examine the role of TIM-1 and TFs in Breg differentiation and regulatory module expression. B cells can also express various proinflammatory cytokines in autoimmune and infectious settings that strongly promote inflammatory responses. No phenotype for such effector B cells (Beff) has been established, and it is unclear whether the various cells described, are distinct or inter-related. Major aspects of Beff biology are completely unknown, including how differentiation and cytokine expression are regulated. We have discovered that: 1) TIM-4 identifies Beff that express IFNγ and IL-17 and accelerate allograft rejection. 2) IL-17 is notably, both a potent effector cytokine, and is also required for development of the Beff inflammatory program. Loss of B cell IL-17 not only reverses their inflammatory role, but also, inhibits the immune response, promoting allograft tolerance. 3) TIM-4 ligation inhibits proinflammatory cytokine expression. Based on our novel preliminary data, this PPG will utilize autoimmune and allograft models to test the central hypothesis that TIM-1 and TIM-4, respectively, are unifying markers for Bregs and Beff and regulate expression of TFs and other molecules important for their development and function. This will be addressed in 3 interactive and mutually supportive projects: Project 1: Role of Tim-1 and Bregs in Tolerance and Auto- immunity; Project 2: Immunoregulation by TLR-activated TIM-1+ ProB Cells in Transplantation; and Project 3: Inflammatory B Cells Defined by TIM-4 in the Alloimmune Response. This understanding is key to developing clinically relevant approaches to selectively target Beff and Bregs to enhance or inhibit the immune response.

除了体液免疫外，B 细胞通过抗原在塑造 T 效应反应中发挥着重要作用呈现、共刺激和细胞因子的产生。因此，B 细胞耗竭可改善自身免疫性糖尿病和小鼠关节炎，并迅速改善人类的 RA 和 MS，并且结果与下降无关自身抗体。相比之下，在人类和小鼠中，B 细胞耗竭也会恶化自身免疫，并可能分别促进肾移植和心脏移植患者的急性排斥反应和慢性血管病变。这些研究表明 B 细胞可以增强或抑制炎症反应。对此，转让各种 B 细胞亚群可以通过 IL-10 以及越来越多的其他细胞抑制自身免疫和同种异体移植排斥机制。然而，这些 Breg 缺乏通用表型或主转录因子 (TF) 阻碍了该领域。目前尚不清楚这些不同的细胞是否不同或相互关联，或者是什么调节它们的分化或细胞因子表达。我们的初步数据表明：1）TIM-1 是一个包容性标记 IL-10+ 布雷格斯。 2) B 细胞上完整的 TIM-1 信号传导调节 TF 和各种调节因子的表达分子（“调节模块”）。这使我们能够测试它们在 Breg 分化和功能中的作用。 3）我们也显示 CpG 激活的 Pro-B 细胞转移超过由成熟 Breg 后代介导的有效抑制不同部位表现出不同的作用机制。祖代和子代都是TIM-1+，这使我们能够检查 TIM-1 和 TF 在 Breg 分化和调节模块表达中的作用。 B 细胞还可以在自身免疫和感染环境中表达各种促炎细胞因子，强烈促进炎症反应。尚未确定此类效应 B 细胞 (Beff) 的表型，目前还不清楚所描述的各种细胞是不同的还是相互关联的。 Beff 生物学的主要方面完全未知，包括如何调节分化和细胞因子表达。我们有发现：1) TIM-4 识别表达 IFNγ 和 IL-17 并加速同种异体移植排斥的 Beff。 2) IL-17 值得注意的是，它既是一种有效的效应细胞因子，也是 Beff 炎症发展所必需的程序。 B 细胞 IL-17 的缺失不仅会逆转其炎症作用，还会抑制免疫反应，促进同种异体移植耐受。 3) TIM-4 连接抑制促炎细胞因子的表达。基于我们新的初步数据，该 PPG 将利用自身免疫和同种异体移植模型来测试中心假设 TIM-1 和 TIM-4 分别是 Bregs 和 Beff 的统一标记并调节转录因子和其他对其发育和功能重要的分子的表达。这将在 3 个互动且相互支持的项目：项目 1：Tim-1 和 Bregs 在宽容和自动中的作用免疫;项目2：TLR激活的TIM-1+ ProB细胞在移植中的免疫调节；和项目 3：同种免疫反应中 TIM-4 定义的炎症 B 细胞。这种理解是发展的关键临床相关方法选择性地针对 Beff 和 Bregs 以增强或抑制免疫反应。