Mechanism of anti-CD45 induced transplantation tolerance

抗CD45诱导移植耐受的机制

• 批准号: 7599695
• 负责人: JAMES FRANCIS MARKMANN
• 金额: $ 38.57万
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7599695
• 关键词: Adult; Allografting; Animals; Antibodies; Antibody Formation; Antigens; B-Cell Activation; B-Lymphocytes; Cell physiology; Cells; Data; Development; Doctor of Philosophy; Equilibrium; Generations; Graft Survival; Human; Immune system; Immunosuppression; Immunosuppressive Agents; In Vitro; Investigation; Life; Link; Lymphocyte; Mediating; Modeling; Nature; PTPRC gene; Pathway interactions; Peripheral; Preclinical Testing; Primates; Process; Production; Property; Reagent; Reporting; Research Personnel; Role; Series; Signal Transduction; T-Cell Activation; T-Lymphocyte; Thymus Gland; Time; Transgenic Model; Translating; Transplantation; Transplantation Tolerance; Treatment Protocols; Up-Regulation; base; cell motility; clinical application; clinically relevant; design; in vivo; insight; interest; novel; programs; reconstitution; tool; trafficking

In the current proposal, we investigate the mechanisms underlying transplantation tolerance induced by treatment with anti-CD45RB antibody. This agent is of considerable interest based on a number of attractive properties, including: 1) that a short course of anti-CD45RB results in long-lived transplantation tolerance in experimental animals, 2) that it may be unique in its ability to reverse ongoing rejection and still result in tolerance, 3) that it may synergize with costimulatory blockade, and 4) that it may exert a negative regulatory signal to T cells through up regulation of CTLA-4. Because of these unique attributes, recently there has developed a renewed enthusiasm for evaluating humanized or human anti-CD45 reagents in primate preclinical testing as a component of a regimen to induce transplant tolerance. Despite extensive study at the cellular level on the CD45's role in T cell activation, the mechanism of tolerance induced by anti CD45RB antibody in vivo is poorly understood. This fact is underscored by two novel and unexpected observations we recently made regarding its in vivo action: first is that tolerance induced by anti-CD45RB is thymus dependent and acts through generation of antigen specific thymus derived T-regs; and second is that tolerance depends on the presence of host B lymphocytes. These findings may make this agent unique among tolerance inducing antibody regimens. Moreover, the fact that anti-CD45RB induced tolerance is centrally mediated further heightens interest in its potential as a unique agent for clinical application. To integrate our preliminary findings into a cohesive model explaining the tolerogenic property of anti-CD45RB, we develop a model to explain the B cell dependent state of central tolerance induced by this agent. Studies in the proposal that dissect the immunological mechanism by which anti-CD45RB therapy leads to transplantation tolerance are facilitated by use of a TcR transgenic model of allograft rejection developed in our lab. This approach allows precise definition of the activity of graft specific T cells and antigen specific T-regs in vivo. Further understanding of the tolerogenic properties of anti-CD45RB therapy in the context of our preliminary data will not only provide insight into the action of this potentially clinically relevant agent, but also may define novel pathways of tolerance induction in vivo.

在目前的建议中，我们研究了诱导移植耐受的机制， 用抗CD 45 RB抗体治疗。该代理是相当大的兴趣，基于一些 有吸引力的特性，包括：1）抗CD 45 RB的短期疗程导致长期移植 实验动物的耐受性，2）它可能是独特的能力，以扭转正在进行的排斥反应， 导致耐受性，3）它可能与共刺激阻断协同作用，以及4）它可能产生负效应。 通过上调CTLA-4向T细胞提供调节信号。由于这些独特的属性， 人们对评价人源化或人抗CD 45试剂重新产生了热情， 灵长类动物临床前试验作为诱导移植耐受方案的组成部分。 尽管在细胞水平上对CD 45在T细胞活化中的作用进行了广泛的研究，但CD 45在T细胞活化中的作用机制仍不清楚。 抗CD 45 RB抗体在体内诱导的耐受性知之甚少。这一事实得到两个方面的强调 我们最近对它的体内作用进行了新的和意想不到的观察：首先是耐受性， 抗CD 45 RB诱导的免疫应答是胸腺依赖性的，通过产生抗原特异性胸腺发挥作用 第二是耐受性取决于宿主B淋巴细胞的存在。这些 这一发现可能使这种药物在诱导耐受性的抗体方案中独一无二。此外，事实上， 抗CD 45 RB诱导的耐受性是中枢介导的，这进一步提高了对其作为一种独特的免疫调节剂的潜力的兴趣。 用于临床应用。 将我们的初步发现整合到一个内聚模型中，解释 抗CD 45 RB，我们建立了一个模型，以解释由这种诱导的中枢耐受的B细胞依赖状态。 剂抗CD 45 RB治疗的免疫学机制研究 通过使用同种异体移植排斥的TcR转基因模型促进了导致移植耐受 在我们的实验室里开发的。这种方法允许精确定义移植物特异性T细胞的活性， 体内抗原特异性T细胞。进一步了解抗CD 45 RB治疗的致耐受性 在我们的初步数据的背景下，不仅可以深入了解这种潜在的临床作用， 相关试剂，而且还可以定义体内耐受诱导的新途径。