Mechanisms of B cell-Dependent Transplantation Tolerance

B 细胞依赖性移植耐受的机制

• 批准号: 10062841
• 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/10062841
• 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; 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.

项目总结/摘要 长期以来，B细胞被认为具有通过向T细胞呈递抗原来促进免疫的主要职责。 细胞并产生抗体。最近，已经认识到，类似于免疫球蛋白的T细胞臂， 在适应性免疫应答中，B细胞臂承担着重要的调节责任。这首先是 在缺乏B细胞使疾病恶化的实验性自身免疫模型中，在 在移植竞技场中，我们首先证明了移植耐受模型（基于抗CD 45 RB抗体 治疗）依赖于B细胞的存在。自从这一发现以来，一些研究人员已经 证实了这一特性的普遍性，显示使用其他耐受原性的类似B细胞要求。 方案包括共刺激阻断，抗TIM-1和抗TIM-4，我们最近报道了 抗-CD 45 RB和抗-TIM-1的组合在更严格的菌株组合中表现相似。这些 模型提供了机会来描述BELINE的作用机制，检查它们在排斥反应中的作用， 和耐受性，并开始探索其作为细胞治疗的潜力。 在上一个资助期内，我们在确定贝伐他汀的体内作用方面取得了重大进展。一些 为目前的建议奠定基础的关键发现包括抗CD 45 RB和抗CD 45 RB诱导的耐受性， TIM-1处理是B细胞依赖性的，并且可以从耐受宿主过继转移到两种B细胞 缺陷和免疫学上充满的未处理小鼠。我们也是第一个报道抗体诱导的 耐受性和布雷格耐受性的过继转移依赖于宿主TcB。此外，我们最近 确定在我们的耐受性模型中，TGF-β是耐受性发展所必需的，特别是，B 细胞分泌TGF-β是必需的。这提供了一个自然的联系之间的Bendy和Tendy，将被解剖 在目标I的拟议研究中进一步。我们最近启动了TLR配体激活的幼稚B细胞的研究 其也表现出延长移植物存活的调节特性。在目的II中，比较 这些细胞与那些从耐受宿主中回收的细胞。最后，在Aim III中，我们开始探索 体外扩增的β-内酰胺酶（eB内酰胺酶），以促进我们的机制分析，并开始评估 作为控制同种异体免疫和自身免疫的手段的BcR的翻译潜力。