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

• 批准号: 9751742
• 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
• 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/9751742
• 关键词: Acute; Address; Adoptive Transfer; Allograft Tolerance; Allografting; Anti-inflammatory; Antibodies; Antigen Presentation; Autoantibodies; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Biology; Cell Transplantation; Cell Transplants; 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; 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

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细胞还起着重要作用 表现，共刺激和细胞因子产生。那，B细胞耗竭可以改善自身免疫性糖尿病 小鼠的关节炎，并迅速改善人类的RA和MS，结果与下降无关 自动抗体。相反，在人和小鼠中，B细胞的耗竭也会恶化自身免疫性，并且可以 分别促进肾脏和心脏移植患者的急性排斥和慢性血管病。这些 研究表明，B细胞可以增强或抑制炎症反应。在这方面，转移 各种B细胞子集可以通过IL-10抑制自身免疫性和同种异体移植排斥，并越来越多的其他列表 机制。但是，缺乏这些Bregs的通用表型或主转录因子（TF）具有 阻碍了领域。这些不同的细胞是不同的还是相互关联的，或者是什么调节是尚不清楚的 它们的分化或细胞因子表达。我们的初步数据显示：1）TIM-1是包容性标记 IL-10+ Bregs。 2）在B细胞上完整的TIM-1信号传导调节TF和各种调节的表达 分子（“调节模块”）。这使我们能够测试他们在布雷格分化和功能中的作用。 3）我们也 表明CpG激活的pro-B细胞转移超过池抑制，由成熟的Breg后代介导 在不同位置表现出不同的作用机理。祖细胞和后代都是tim-1+， 这使我们能够检查TIM-1和TF在布雷格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性环境中表达各种促炎性细胞因子 强烈促进炎症反应。尚未确定这种效应B细胞（BEFF）的表型， 目前尚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，既有有效的效应细胞因子，也是发育炎症的必不可少的 程序。 B细胞IL-17的丧失不仅逆转其炎症作用，而且还抑制免疫反应， 促进同种群耐受性。 3）TIM-4连接抑制促炎性细胞因子的表达。 基于我们新颖的初步数据，该PPG将利用自身免疫和同种异体移植模型来测试 中央假设分别是TIM-1和TIM-4分别为Bregs和Beff统一标记和调节 TF和其他分子的表达对于它们的发育和功能很重要。这将在 3互动和相互支持的项目：项目1：TIM-1和Bregs在宽容和自动中的作用 免疫;项目2：移植中TLR激活的TIM-1+概率细胞免疫调节；和项目3： 在同种免疫反应中由Tim-4定义的炎性B细胞。这种理解是发展的关键 临床上相关的方法，以选择性地靶向BEFF和BREG，以增强或抑制免疫响应。