Mechanism of anti-CD45 induced transplantation tolerance

描述（由申请人提供）：在本提案中，我们研究了抗CD 45 RB抗体治疗诱导移植耐受的潜在机制。该试剂基于许多有吸引力的性质而引起相当大的兴趣，包括：1）抗-CD 45 RB的短疗程导致实验动物中的长期移植耐受性，2）其在逆转正在进行的排斥并仍然导致耐受性的能力方面可能是独特的，3）其可以与共刺激阻断协同作用，和4）它可以通过上调CTLA-4向T细胞施加负调节信号。由于这些独特的属性，最近人们对在灵长类动物临床前试验中评价人源化或人抗CD 45试剂作为诱导移植耐受方案的组成部分重新产生了热情。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，但抗CD 45 RB抗体在体内诱导耐受的机制知之甚少。我们最近关于其体内作用的两个新的和意想不到的观察结果强调了这一事实：第一个是抗CD 45 RB诱导的耐受性是胸腺依赖性的，并通过产生抗原特异性胸腺衍生的T细胞发挥作用;第二个是耐受性取决于宿主B淋巴细胞的存在。这些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，抗CD 45 RB诱导的耐受性是中枢介导的这一事实进一步提高了对其作为临床应用的独特试剂的潜力的兴趣。为了将我们的初步研究结果整合到解释抗CD 45 RB致耐受性特性的内聚模型中，我们开发了一个模型来解释该试剂诱导的中枢耐受性的B细胞依赖性状态。本实验室建立的TcR转基因同种异体移植排斥反应模型有助于深入研究抗CD 45 RB治疗导致移植耐受的免疫学机制。该方法允许精确定义移植物特异性T细胞和抗原特异性T细胞在体内的活性。在我们的初步数据背景下，进一步了解抗CD 45 RB治疗的致耐受性，不仅可以深入了解这种潜在的临床相关药物的作用，而且还可以定义体内耐受诱导的新途径。

DESCRIPTION (provided by applicant): 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.