Mechanisms of B Cell-Dependent Transplantation Tolerance

描述（由申请方提供）：调节对自身抗原和外来病原体的免疫应答是宿主存活的组成部分。所涉及的天然调节途径也可能提供干预不期望的免疫应答的机会，例如发生于同种异体移植物的免疫应答。这种方法的吸引力在应用调节性T细胞（Tcells）以促进患者移植存活的热情中显而易见。最近的证据表明，平行的调节途径可能存在于体液免疫反应的手臂，虽然确切的细胞参与和调节机制尚未得到充分的表征。尽管有令人信服的证据表明调节性B细胞（BCRs）在非移植环境（自身免疫、感染性疾病和骨髓移植/GVHD）中的作用，但B细胞或BCRs在维持诱导的移植耐受中的明确作用尚未得到充分确立。在最后一个资助期间，我们进行了意外观察，即抗体诱导的移植耐受的充分研究模型取决于B淋巴细胞的存在，并且模型中的移植物延长可通过TIM-1+ B细胞转移至第二宿主，证明了布雷格活性。在拟议的研究中，我们将使用在前一个资助期开发的模型来描述Bcadherin对移植耐受性的贡献。在目的I中，我们重点关注Bleg抑制天然Teff应答的机制，并检查布雷格抗原特异性，表征布雷格诱导的免疫应答特征变化，并定义免疫调节细胞因子（IL-10和TGF-β）的作用。在目的II中，我们将利用我们的发现，即抗CD 45 RB诱导的耐受性依赖于TclG和B细胞，以探索Treg发育由BclG促进或TclG和BclG合作促进移植物接受的可能性。最后，目的III检查共刺激分子TIM-1对抗CD 45 RB诱导的耐受性的贡献，并将依赖于我们的合作者Terry Strom博士产生的新TIM 1-/-系。总的来说，这些研究将进一步加深我们对调节性B细胞对移植耐受的独特贡献的理解。 公共卫生相关性：T细胞介导的耐受和排斥调节（由TdR）现已得到充分确立。在目前的工作中，我们探讨了潜在的平行调节途径的体液手臂的适应性免疫反应的贝伐他汀。初步数据表明，B细胞对许多致耐受性抗体方案诱导的耐受性至关重要。我们将研究这些模型中Bceptin介导耐受性的机制以及它们如何与Tceptin合作。

DESCRIPTION (provided by applicant): Regulation of the immune response to both self-antigens and foreign pathogens is integral to host survival. The natural regulatory pathways involved may also afford the opportunity to intercede in undesirable immune responses such as those occurring to allogeneic transplants. The attractiveness of this approach is evident in the enthusiasm for applying regulatory T cells (Tregs) to promote transplant survival in patients. Recent evidence suggests that parallel regulatory pathways may exist in the humoral arm of the immune response though the exact cells involved and the mechanisms of regulation are yet to be fully characterized. Despite the convincing evidence for regulatory B cells (Bregs) in non-transplant settings (autoimmunity, infectious disease, and bone marrow transplant/GVHD), a clear role for B cells or Bregs in the maintenance of induced transplant tolerance has not yet been well-established. During the last funding period we made the unexpected observation that a well-studied model of antibody induced transplantation tolerance depends on the presence of B lymphocytes and that graft prolongation in the model was transferrable to secondary hosts by TIM-1+ B cells, demonstrating Breg activity. In the proposed studies, we will characterize the contribution of Bregs to transplantation tolerance using models developed in the previous funding period. In Aim I, we focus on the mechanisms by which Bregs suppress the response of na¿ve Teff and examine Breg antigen specificity, characterize Breg induced changes in the character of the immune response and define the role of immunomodulatory cytokines (IL-10 and TGF-?). In Aim II, we will take advantage of our finding that anti-CD45RB-induced tolerance is dependent on both Tregs and B cells to explore the possibility that Treg development is fostered by Bregs or that Tregs and Bregs collaborate to promote graft acceptance. Finally, Aim III examines the contribution of the costimulatory molecule TIM-1 to tolerance induced by anti-CD45RB and will rely on a new TIM1-/- line generated by our collaborator, Dr Terry Strom. Collectively, these studies will further our understanding of the unique contribution of regulatory B cells to transplantation tolerance. PUBLIC HEALTH RELEVANCE: T cell mediated regulation (by Tregs) of tolerance and rejection is now well-established. In the current work we explore the potential for parallel regulatory pathways in the humoral arm of the adaptive immune response by Bregs. Preliminary data suggest that B cells are critical to tolerance induced by a number of tolerogenic antibody regimens. We will study the mechanisms by which Bregs mediated tolerance in these models and how they collaborate with Tregs.