Mechanism of anti-CD45 induced transplantation tolerance

描述(申请人提供)：在当前的提案中，我们调查了抗CD45RB抗体治疗诱导移植耐受的机制。这种药物具有许多吸引人的特性，包括：1)短程抗CD45RB可以导致实验动物长期的移植耐受，2)它可能是独一无二的逆转持续排斥反应并仍然导致耐受的能力，3)它可能与共刺激阻断协同作用，4)它可能通过上调CTLA-4对T细胞施加负面调节信号。由于这些独特的属性，最近人们重新热衷于在灵长类动物的临床前试验中评估人源化或人源性抗CD45试剂，作为诱导移植耐受方案的组成部分。尽管在细胞水平上对CD45Rb的S在T细胞活化中的作用进行了广泛的研究，但抗CD45Rb抗体在体内诱导耐受的机制尚不清楚。我们最近关于其体内作用的两个新的和意想不到的观察强调了这一事实：第一，抗CD45RB诱导的耐受性是胸腺依赖的，并通过产生抗原特异性胸腺来源的T-regs起作用；第二，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的抗体方案中独树一帜。此外，抗CD45RB诱导的耐受是由中央调节的，这一事实进一步增强了人们对其作为一种独特的临床应用药物的兴趣。为了将我们的初步发现整合到一个解释抗CD45RB的耐受特性的内聚模型中，我们开发了一个模型来解释这种药物诱导的中枢耐受的B细胞依赖状态。通过使用我们实验室建立的同种异体移植排斥反应的TCR转基因模型，剖析抗CD45RB治疗导致移植耐受的免疫学机制的建议中的研究是便利的。这种方法可以精确地定义体内移植物特异性T细胞和抗原特异性T-regs的活性。在我们初步数据的背景下，进一步了解抗CD45RB治疗的耐受特性，不仅将为这种潜在的临床相关药物的作用提供洞察，而且还可能定义体内诱导耐受的新途径。

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.