Mechanisms of B cell-Dependent Transplantation Tolerance

B 细胞依赖性移植耐受的机制

• 批准号: 10308033
• 负责人: JAMES FRANCIS MARKMANN
• 金额: $ 50.89万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308033
• 关键词: Adoptive Transfer; Allografting; Antibodies; Antibody Therapy; Antigens; Area; Autoimmune; Autoimmunity; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Cardiovascular system; Cell Differentiation process; Cell secretion; Cell surface; Cells; Charge; Clinical; Clinical assessments; Colitis; Data; Dependence; Development; Disease; Exhibits; Experimental Autoimmune Encephalomyelitis; Exposure to; Funding; Generations; Graft Survival; Growth Factor; Helper-Inducer T-Lymphocyte; Hypersensitivity; IL2RA gene; Immune response; Immunity; Immunobiology; Immunologics; Immunology; Immunotherapeutic agent; In Vitro; Interleukin-10; Interleukin-4; Investigation; Knowledge; Ligands; Link; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Pathway interactions; Patients; Population; Production; Property; Regimen; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Reporting; Research Personnel; Role; Self Tolerance; Series; Signal Transduction; Skin; Specificity; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Tissue Transplantation; Transforming Growth Factor beta; Transgenic Mice; Transplantation; Transplantation Tolerance; Work; adaptive immune response; arm; base; clinical application; clinical investigation; cytokine; experimental study; heart allograft; humoral immunity deficiency; immunoregulation; in vivo; interest; islet; islet allograft; isoimmunity; migration; nano-string; novel; organ transplant rejection; prevent; programs; receptor; response; translational potential; transplant model

PROJECT SUMMARY / ABSTRACT B cells have long been regarded as having the primary duties of promoting immunity by presenting antigen to T cells and producing antibody. More recently it has been appreciated that, similar to the T cell arm of the adaptive immune response, the B cell arm is charged with significant regulatory responsibility. This was first appreciated in experimental autoimmunity models in which the absence of B cells exacerbated disease. In the transplant arena, we first demonstrated a model of transplant tolerance (based on anti-CD45RB antibody therapy) that was dependent on the presence of B cells. Since this finding, a number of investigators have substantiated the generality of this property, showing a similar B cell requirement using other tolerogenic regimens including co-stimulation blockade, anti-TIM-1, and anti-TIM-4, and we recently reported the combination of anti-CD45RB and anti-TIM-1 to behave similarly in more stringent strain combinations. These models provide opportunity to delineate the mechanism of action of Bregs, to examine their role in rejection and tolerance, and to begin to explore their potential as a cellular therapeutic. During the last funding period we made significant progress in defining the in vivo action of Bregs. Some of the key findings that set the stage for the current proposal include that tolerance induced by anti-CD45RB and anti- TIM-1 treatment is B cell dependent and can be adoptively transferred from tolerant hosts to both B cell deficient and immunologically replete untreated mice. We were also the first to report that antibody induced tolerance and adoptive transfer of Breg tolerance is dependent on host Tregs. In addition, we recently determined that in our tolerance model, TGF-β is required for development of tolerance and, specifically, that B cell secretion of TGF-β is essential. This provides a natural link between Bregs and Tregs and will be dissected further in the proposed studies of Aim I. We recently initiate studies of naïve B cells activated by TLR ligands that also exhibit graft survival prolonging regulatory properties. In Aim II, compare the mechanism of action of these cells with those recovered from tolerance hosts. Finally, in Aim III, we begin to explore the potential of in vitro expanded Bregs (eBregs) both to facilitate our mechanistic analyses and to begin to assess the translational potential of Bregs as a means to control alloimmunity and autoimmunity.

项目摘要/摘要 长期以来，B细胞一直被认为具有通过向T细胞递呈抗原来促进免疫的主要职责 细胞和产生抗体。最近，人们意识到，与T细胞臂类似， 在适应性免疫反应中，B细胞臂承担着重要的调节责任。这是第一次 在实验性自身免疫模型中受到赞赏，在该模型中，B细胞的缺失会加剧疾病。在 在移植领域，我们首先展示了一个移植耐受模型(基于抗CD45RB抗体 治疗)，这取决于B细胞的存在。自这一发现以来，一些调查人员已经 证实了这一特性的普遍性，显示出使用其他耐受性的类似B细胞需求 方案包括共刺激阻断，抗TIM-1和抗TIM-4，我们最近报道了 抗CD45RB和抗TIM-1的组合在更严格的菌株组合中表现相似。这些 模型提供了描述Bregs的作用机制，检查它们在排斥中的作用的机会 和耐受性，并开始探索其作为细胞治疗的潜力。 在上一次资助期间，我们在确定Bregs的体内作用方面取得了重大进展。其中一些 为当前提案奠定基础的关键发现包括，抗CD45RB和抗CD45RB诱导的耐受 TIM-1治疗依赖于B细胞，可以过继地从耐受宿主转移到两个B细胞 缺乏和免疫充足的未经处理的小鼠。我们也是第一个报道抗体诱导 BREG耐性的耐性和采用转移依赖于寄主Tregs。另外，我们最近 确定在我们的耐受性模型中，转化生长因子-β是形成耐受性所必需的，具体地说，B 细胞分泌转化生长因子-β是必不可少的。这在Bregs和Tregs之间提供了一种天然的联系，并将被解剖 在AIM I的拟议研究中，我们最近启动了TLR配体激活的幼稚B细胞的研究 这也显示了移植物的存活时间延长了调节特性。在AIM II中，比较了 这些细胞与从耐受宿主中回收的细胞相同。最后，在目标三中，我们开始探索In的潜力 体外扩增的Bregs(EBregs)既方便了我们的机制分析，也开始评估 Bregs作为控制同种异体免疫和自身免疫的翻译潜能。