Inflammatory B Cells Defined by TIM-4 in the Alloimmune Response

TIM-4 在同种免疫反应中定义的炎症 B 细胞

• 批准号: 9542016
• 负责人: DAVID M ROTHSTEIN
• 金额: $ 37.15万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9542016
• 关键词: Acute; Address; Affect; Allograft Tolerance; Allografting; Alpha Cell; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Attenuated; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Biology; Bone Marrow; Cell Communication; Cell Shape; Cell physiology; Cells; Chronic; Clinical; Cytoplasmic Tail; Data; Development; Disease; Exhibits; Experimental Autoimmune Encephalomyelitis; Generations; Genetic Transcription; Goals; Graft Rejection; Heart Transplantation; Human; Humoral Immunities; Immune Tolerance; Immune response; Individual; Infection; Inflammation Mediators; Inflammatory; Integrins; Interferon Type II; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-6; Isoantibodies; Knockout Mice; Left; Ligation; MS4A1 gene; Mus; Outcome; Patients; Pattern; Peptides; Phenotype; Plasma Cells; Play; Production; Regulation; Regulator Genes; Regulatory Element; Rodent; Role; Signal Pathway; Signal Transduction; T-Lymphocyte; TNF gene; Therapeutic; Time; Transplant Recipients; Transplantation; Vascular Diseases; Work; allograft rejection; antimicrobial; cytokine; design; immunoregulation; improved; insight; islet allograft; kidney allograft; nano-string; novel; programs; proteoglycan induced arthritis; response; transcription factor; transcriptome; transcriptome sequencing; tumor

It is clear that B cells play important Ab-independent roles either promoting or regulating immune responses through the opposing activity of regulatory B cells (Bregs) and proinflammatory effector B cells (Beff). This is likely to explain observations that B cell depletion with anti-CD20 can rapidly improve autoimmune diseases, such as RA and MS, without depleting auto-Ab. Yet in other patients, autoimmunity is worsened. Moreover, peri-transplant depletion of B cells can markedly increase acute rejection in renal allograft recipients and chronic vasculopathy in heart transplantation. These contradictory results are likely due to the presence of both Bregs and Beff, and not knowing which predominates at a given time, in a given clinical setting, or in a given patient. A similar dichotomy is present in mice, where B cell depletion/deficiency can either inhibit or promote autoimmunity and allograft rejection. We contend that targeting B cells in autoimmune and transplant patients would have far better outcomes if Beff were selectively targeted and Bregs were left intact. Unfortunately, little is known about Bregs, and even less is known about Beff cells. In mice, B cells expressing pro-inflammatory cytokines such as IL-6 and IFNγ play a key role promoting autoimmune responses in EAE and proteoglycan- induced arthritis. Moreover, in response to various infections, B cells exhibit rapid and transient innate-like protective responses through expression of TNFα, IFNγ, IL-2, and IL-17. However, it is unknown whether, or how, any of these responses relate to one another, because no phenotype for such Beff has been established and individual cytokines were examined in isolation. Thus, major aspects of Beff biology, including what regulates their differentiation and cytokine expression, are completely unknown. We have now discovered that TIM-4 identifies Beff that express inflammatory cytokines including IFNγ and IL-17, and accelerate allograft rejection. Eliminating expression of these cytokines by B cells, reverses this proinflammatory role, but can also markedly inhibit the alloimmune response and promote tolerance. Moreover, some cytokines affect the expression of others. Notably, IL-17 is not only a potent effector cytokine, but is essential for Beff to develop an inflammatory rather than regulatory program. Finally, TIM-4 ligation inhibits expression of proinflammatory cytokines. Understanding the role of TIM-4+ Beff in priming the immune response and identifying how this response can be regulated to promote tolerance, are key and unique aspects of this proposal. These results are likely to provide a unifying framework for understanding Beff cells, and will have major impact on the field. In Aim 1 we will determine whether TIM-4+ Beff express a “proinflammatory module” comprised of additional effector molecules and transcriptional regulatory elements, and determine key aspects of its regulation. In Aim 2 we will define key mechanisms by which TIM-4+ Beff promote allograft rejection. In Aim 3 we will determine how TIM-4 signaling regulates expression of the Beff pro-inflammatory module. This work will greatly enhance our understanding of Beff biology and provide therapeutic insights highly relevant to immune tolerance.

显然，B细胞扮演着重要的AB独立角色，促进或控制免疫调查 通过调节B细胞（BREG）和促炎效应B细胞（BEFF）的相对活性。这是 可能解释了抗CD20的B细胞部署可以迅速改善自身免疫性疾病的观察结果， 例如RA和MS，而无需耗尽自动AB。然而，在其他患者中，自身免疫会恶化。而且， B细胞的移植侧植物消耗可以显着增加同种异体移植受体中的急性排斥反应和 心脏移植中的慢性血管病。这些矛盾的结果可能是由于两者的存在 Bregs和Beff，不知道在给定时间，在给定的临床环境中或在给定的时间内占主导地位 病人。在小鼠中也存在类似的二分法，其中B细胞部署/缺乏可以抑制或促进 自身免疫性和同种异体拒绝。我们认为，靶向自身免疫和移植患者中的B细胞 如果将BEFF选择性靶向并且Bregs完整，将会取得更好的结果。不幸的是，很少 关于Bregs知之甚少，对Beff细胞的了解较少。在小鼠中，表达促炎的B细胞 IL-6和IFNγ等细胞因子起着关键作用，促进EAE和蛋白聚糖中的自身免疫反应 诱发关节炎。此外，为了响应各种感染，B细胞表现出快速而瞬时的样子样 通过表达TNFα，IFNγ，IL-2和IL-17的保护反应。但是，尚不清楚是还是 这些响应中的任何一个彼此之间的关系中的任何一个，因为尚未建立这种BEFF的表型 分别检查了单个细胞因子。这是Beff生物学的主要方面，包括 调节它们的分化和细胞因子表达是完全未知的。我们现在发现 TIM-4识别表达包括IFNγ和IL-17在内的炎症细胞因子的BEFF，并加速了异形 拒绝。消除B细胞对这些细胞因子的表达，逆转这种促炎作用，但也可以 明显抑制同种免疫反应并促进耐受性。此外，某些细胞因子会影响 他人的表达。值得注意的是，IL-17不仅是潜在效应子细胞因子，而且对于Beff而言， 炎症而不是监管计划。最后，TIM-4连接抑制促炎的表达 细胞因子。了解TIM-4+ BEFF在启动免疫反应并确定这一点的作用 可以调节响应以促进宽容，是该提案的关键和独特方面。这些结果 可能会提供一个统一的框架来理解Beff细胞，并对该领域产生重大影响。 在AIM 1中，我们将确定tim-4+ beff是否表示附加的“促炎模块” 效应子分子和转录调节元件，并确定其调节的关键方面。目标 2我们将定义TIM-4+ BEFF促进同种异体移植排斥的关键机制。在AIM 3中，我们将确定 TIM-4信号传导如何调节BEFF促炎模块的表达。这项工作将大大改善 我们对BEFF生物学的理解，并提供与免疫耐受性高度相关的热见解。