Inflammatory B cells defined by TIM-4 in the Alloimmune response

同种免疫反应中 TIM-4 定义的炎症 B 细胞

• 批准号: 10455071
• 负责人: DAVID M ROTHSTEIN
• 金额: $ 41.58万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455071
• 关键词: Acute; Address; Affect; Allograft Tolerance; Allografting; Anti-Inflammatory Agents; Antigen Presentation; Attenuated; Autoimmune; Autoimmune Diseases; 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; 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; Monoclonal Antibodies; Mus; 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; anti-CD20; antimicrobial; cytokine; design; immunoregulation; improved; insight; islet allograft; kidney allograft; nano-string; novel; programs; proteoglycan induced arthritis; response; transcription factor; transcriptome; transcriptome sequencing; tumor

Summary: It is clear that B cells play important Ab-independent roles either promoting or inhibiting 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 auto- immune diseases, such as RA and MS, without depleting auto-Ab. Yet in other patients, disease 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 results 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.

摘要：很明显，B细胞在促进或抑制免疫方面发挥着重要的抗体非依赖性作用 调节性B细胞(Bregs)和促炎效应B细胞的相反活性反应 (Beff)。这可能解释了用抗CD20抗体去除B细胞可以迅速改善自身- 免疫性疾病，如类风湿性关节炎和多发性硬化症，不耗尽自身抗体。然而，在其他患者中，疾病会恶化。 此外，移植围术期B细胞的去除可显著增加肾移植受者的急性排斥反应。 心脏移植中的慢性血管病变。这些相互矛盾的结果很可能是由于 Bregs和Beff，并且不知道在给定的时间、在给定的临床环境或在 有耐心的话。在小鼠中也存在类似的二分法，在这种情况下，B细胞枯竭/缺乏可以抑制或 促进自身免疫和同种异体排斥反应。我们认为在自身免疫和移植中靶向B细胞 如果有选择地以Beff为目标，而Bregs保持不变，患者会有更好的结果。不幸的是， 人们对Bregs知之甚少，对Beff细胞更是知之甚少。在小鼠中，表达PRO-1的B细胞 炎性细胞因子如IL-6和干扰素γ在促进自身免疫反应中起关键作用 蛋白多糖诱导的关节炎。此外，在对各种感染的反应中，B细胞表现出快速和短暂的 通过表达肿瘤坏死因子α、干扰素γ、IL-2和IL-17的先天保护性反应。然而，它是未知的 这些反应中的任何一个是否或如何相互关联，因为没有这样的Beff表型 分离检测已建立的和单独的细胞因子。因此，Beff生物学的主要方面，包括 是什么调节它们的分化和细胞因子的表达，是完全未知的。我们现在发现 TIM-4识别表达包括干扰素γ和IL-17在内的炎性细胞因子的BeFf，并促进同种异体移植 拒绝。通过B细胞消除这些细胞因子的表达，逆转这种促炎作用，但也可以 显著抑制同种异体免疫反应，促进免疫耐受。此外，一些细胞因子会影响 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BeFF发展成 煽动性而不是监管计划。最后，TIM-4结扎抑制促炎因子的表达 细胞因子。了解Tim-4+Beff在启动免疫反应中的作用并确定这一过程 可以调节应对措施以促进宽容，这是这项提案的关键和独特方面。这些结果 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是否表达由额外的 效应器分子和转录调控元件，并决定其调控的关键方面。在AIM 2我们将明确Tim-4+Beff促进同种异体移植排斥反应的关键机制。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。这项工作将大大提高 我们对Beff生物学的了解，并提供与免疫耐受性高度相关的治疗见解。