Mechanisms of B cell-Dependent Transplantation Tolerance

B 细胞依赖性移植耐受的机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要长期以来，B 细胞一直被认为具有通过向 T 呈递抗原来促进免疫的主要职责最近人们认识到，类似于 T 细胞臂。适应性免疫反应中，B 细胞臂担负着重要的调节责任。在实验性自身免疫模型中，B 细胞的缺乏会加剧疾病，这一点得到了赞赏。移植领域，我们首先展示了移植耐受模型（基于抗CD45RB抗体疗法）依赖于 B 细胞的存在自这一发现以来，许多研究人员已经开始研究。证实了这一特性的普遍性，显示出使用其他耐受原性的类似 B 细胞要求治疗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。模型提供了描述 Bregs 作用机制的机会，以检查它们在拒绝中的作用和耐受性，并开始探索它们作为细胞治疗的潜力。在上一个资助期间，我们在定义 Bregs 的一些体内作用方面取得了重大进展。为当前提案奠定基础的关键发现包括抗CD45RB和抗CD45RB诱导的耐受性 TIM-1 治疗是 B 细胞依赖性的，可以从耐受宿主过继转移至 B 细胞我们也是第一个报道抗体诱导的小鼠。 Breg的耐受性和过继性转移依赖于宿主Tregs。确定在我们的耐受模型中，TGF-β是耐受发展所必需的，特别是，B TGF-β 的细胞分泌至关重要，这提供了 Breg 和 Tregs 之间的天然联系，并将对其进行剖析。在 Aim I 的拟议研究中，我们进一步开展了由 TLR 配体激活的幼稚 B 细胞的研究还表现出延长移植物存活的调节特性。在目标 II 中，比较了作用机制。最后，在目标 III 中，我们开始探索 in 的潜力。体外扩增 Bregs (eBregs) 既可以促进我们的机制分析，也可以开始评估 Bregs 作为控制同种免疫和自身免疫手段的转化潜力。