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

基本信息

批准号：
10214481
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
项目类别：
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/10214481
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

项目摘要

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独立于抗体的作用。通过调节性 B 细胞 (Breg) 和促炎效应 B 细胞的相反活性做出反应 (Beff)。这可能解释了用抗 CD20 消除 B 细胞可以快速改善自体细胞的观察结果。免疫疾病，如 RA 和 MS，不会耗尽自身抗体，但在其他患者中，疾病会恶化。此外，移植周围 B 细胞的消耗会显着增加同种异体肾移植受者的急性排斥反应和心脏移植中的慢性血管病变这些矛盾的结果可能是由于存在。 Breg 和 Beff，并且不知道在特定时间、特定临床环境或特定情况下哪个占主导地位小鼠中也存在类似的二分法，其中 B 细胞耗尽/缺乏可以抑制或抑制。我们认为，在自身免疫和移植中靶向 B 细胞。如果选择性地针对 Beff 而 Bregs 保持不变，患者将会获得更好的结果。人们对 Bregs 知之甚少，对小鼠体内表达 pro-的 Beff 细胞更是知之甚少。 IL-6 和 IFNγ 等炎症细胞因子在 EAE 和 EAE 中发挥着促进自身免疫反应的关键作用。此外，针对各种感染，B 细胞表现出快速且短暂的反应。通过 TNFα、IFNγ、IL-2 和 IL-17 的表达产生先天性保护反应，但目前尚不清楚。这些反应是否或如何相互关联，因为尚未发现此类 Beff 的表型因此，Beff 生物学的主要方面，包括单独检查。我们现在完全不知道是什么调节它们的分化和细胞因子表达。 TIM-4 识别出表达炎症细胞因子（包括 IFNγ 和 IL-17）的 Beff，并加速同种异体移植消除 B 细胞表达的这些细胞因子可以逆转这种促炎作用，但也可以逆转这种作用。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。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 开发细胞因子至关重要。最后，TIM-4 连接抑制促炎程序的表达。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。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，并确定其调控的关键方面。 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 促炎症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。