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: 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
• 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

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.

除体液免疫外，B细胞通过抗原形成T效应子应答发挥重要作用 呈递、共刺激和细胞因子产生。因此，B细胞耗竭可改善自身免疫性糖尿病 和关节炎，并迅速改善RA和MS在人类，和结果不相关的下跌， 自身抗体相比之下，在人和小鼠中，B细胞耗竭也会使自身免疫恶化， 分别促进肾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。在这方面， 各种B细胞亚群可以通过IL-10抑制自身免疫和同种异体移植排斥，并且越来越多的其他细胞亚群可以通过IL-10抑制自身免疫和同种异体移植排斥。 机制等然而，缺乏一个通用的表型或主转录因子（TF）的这些细菌， 阻碍了这一领域。目前还不清楚这些不同的细胞是不同的还是相互关联的，或者是什么调节了这些细胞的功能。 它们的分化或细胞因子表达。我们的初步数据表明：1）TIM-1是一个包容性的标志物， IL-10+ β-内酰胺酶。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布雷格分化和功能中的作用。3)我们也 显示CpG活化Pro-B细胞转移超过由成熟布雷格后代介导的有效抑制 在不同的位置表现出不同的作用机制。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环境中表达各种促炎细胞因子， 强烈促进炎症反应。尚未建立这种效应B细胞（Beff）的表型， 并且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 是完全未知的，包括分化和细胞因子表达是如何调节的。我们有 发现：1）TIM-4识别表达IFNγ和IL-17并加速同种异体排斥反应的Beff。2)IL-17 值得注意的是，既是一种有效的效应细胞因子，也是Beff炎性细胞因子的发展所必需的。 程序. B细胞IL-17的丧失不仅逆转了它们的炎症作用，而且抑制了免疫应答， 促进同种异体移植耐受。3)TIM-4连接抑制促炎细胞因子表达。 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Beff和Beff的统一标志物， TF和其他对其发育和功能重要的分子的表达。这将在 3个互动和相互支持的项目：项目1：Tim-1和Bethesda在宽容和自动化中的作用 项目2：移植中TLR激活的TIM-1+ ProB细胞的免疫调节;项目3： 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 选择性地靶向Beff和Beside以增强或抑制免疫应答的临床相关方法。