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.

结论：B细胞在促进或抑制免疫应答中发挥重要的非Ab依赖性作用， 通过调节性B细胞（Bcl-2）和促炎效应B细胞的相反活性产生的反应 （Beff）.这可能解释了用抗CD 20去除B细胞可以迅速改善自体免疫的观察结果。 免疫性疾病，如RA和MS，而不消耗自身抗体。然而，在其他患者中，疾病恶化。 此外，肾移植术前后B细胞的耗竭可显著增加肾移植受者的急性排斥反应 和慢性血管病变。这些相互矛盾的结果可能是由于 在给定的时间，在给定的临床环境中，或在给定的临床环境中， 给病人。在小鼠中也存在类似的二分法，其中B细胞耗竭/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，在自身免疫和移植中靶向B细胞， 如果选择性地靶向Beff，而Beff保持完整，患者将获得更好的结果。不幸的是， 对Besides知之甚少，对Beff细胞的了解更少。在小鼠中，表达前- 炎性细胞因子如IL-6和IFNγ在EAE中促进自身免疫应答起关键作用， 蛋白多糖引起的关节炎此外，响应于各种感染，B细胞表现出快速和短暂的 通过表达TNFα、IFNγ、IL-2和IL-17的先天性样保护性应答。但不清楚 这些反应中的任何一个是否或如何相互关联，因为还没有这种Beff的表型被发现。 单独检测已建立的和单个的细胞因子。因此，Beff生物学的主要方面，包括 是什么调节了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鉴定了表达炎性细胞因子包括IFNγ和IL-17并加速同种异体移植Beff， 排斥反应消除B细胞表达的这些细胞因子，逆转了这种促炎作用，但也可以 显著抑制同种免疫反应并促进耐受性。此外，一些细胞因子影响细胞因子的表达。 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，而且是Beff发展免疫系统所必需的。 而非监管计划。最后，TIM-4连接抑制促炎性细胞因子的表达。 细胞因子了解TIM-4+ Beff在引发免疫应答中的作用，并确定这是如何发生的。 可以调节反应，以促进宽容，是这一建议的关键和独特的方面。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是否表达由额外的细胞因子组成的“促炎模块”。 效应分子和转录调控元件，并确定其调控的关键方面。在Aim中 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信号传导如何调节Beff促炎模块的表达。这项工作将大大提高 我们对Beff生物学的理解，并提供与免疫耐受高度相关的治疗见解。