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.

很明显，B 细胞在促进或调节免疫反应方面发挥着重要的独立于抗体的作用 通过调节性 B 细胞 (Bregs) 和促炎效应 B 细胞 (Beff) 的相反活性。这是 可能解释用抗 CD20 消除 B 细胞可以快速改善自身免疫性疾病的观察结果， 例如 RA 和 MS，而不耗尽自身抗体。然而，在其他患者中，自身免疫却恶化了。而且， 移植周围 B 细胞的耗竭可显着增加同种异体肾移植受者的急性排斥反应 心脏移植中的慢性血管病变。这些矛盾的结果可能是由于两者的存在 Bregs 和 Beff，并且不知道在给定时间、给定临床环境或给定情况下哪个占主导地位 病人。小鼠中也存在类似的二分法，其中 B 细胞耗尽/缺乏可以抑制或促进 自身免疫和同种异体移植排斥。我们认为，针对自身免疫和移植患者的 B 细胞 如果有选择地针对 Beff 并保留 Breg 完好无损，结果会好得多。不幸的是，很少 人们对 Breg 细胞了解甚少，而对 Beff 细胞则知之甚少。在小鼠中，B 细胞表达促炎细胞 IL-6 和 IFNγ 等细胞因子在促进 EAE 和蛋白聚糖中的自身免疫反应中发挥着关键作用 诱发关节炎。此外，为了应对各种感染，B 细胞表现出快速且短暂的先天样 通过 TNFα、IFNγ、IL-2 和 IL-17 的表达产生保护性反应。然而，尚不清楚是否，或 这些反应中的任何一个如何相互关联，因为尚未建立此类 Beff 的表型 并单独检查单个细胞因子。因此，贝夫生物学的主要方面，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 识别表达炎症细胞因子（包括 IFNγ 和 IL-17）的 Beff，并加速同种异体移植 拒绝。消除 B 细胞表达这些细胞因子可以逆转这种促炎作用，但也可以 显着抑制同种免疫反应并促进耐受。此外，一些细胞因子影响 他人的表达。值得注意的是，IL-17 不仅是一种有效的效应细胞因子，而且对于 Beff 开发一种 煽动性而非监管性计划。最后，TIM-4 连接抑制促炎细胞的表达 细胞因子。了解 TIM-4+ Beff 在启动免疫反应中的作用并确定其作用机制 可以调节反应以促进宽容，是该提案的关键和独特方面。这些结果 很可能为理解 Beff 细胞提供一个统一的框架，并将对该领域产生重大影响。 在目标 1 中，我们将确定 TIM-4+ Beff 是否表达由额外组成的“促炎模块” 效应分子和转录调控元件，并决定其调控的关键方面。瞄准 2 我们将定义 TIM-4+ Beff 促进同种异体移植排斥的关键机制。在目标 3 中，我们将确定 TIM-4 信号如何调节 Beff 促炎模块的表达。这项工作将大大增强 我们对 Beff 生物学的理解并提供与免疫耐受高度相关的治疗见解。