Mechanisms of B Cell-Dependent Transplantation Tolerance

描述（由申请人提供）：调节对自身抗原和外来病原体的免疫反应对宿主生存是不可或缺的。所涉及的自然调控途径也可能提供了调解不良免疫反应的机会，如那些发生在异体移植中的免疫反应。这种方法的吸引力在应用调节性T细胞（Tregs）促进移植患者存活的热情中是显而易见的。最近的证据表明，平行的调节途径可能存在于免疫反应的体液臂，但具体涉及的细胞和调节机制尚未完全表征。尽管有令人信服的证据表明调节性B细胞（Bregs）在非移植环境（自身免疫、感染性疾病和骨髓移植/GVHD）中存在，但B细胞或Bregs在维持诱导移植耐受中的明确作用尚未得到证实。在上一个资助期间，我们意外地观察到，抗体诱导的移植耐受模型依赖于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细胞转移到继代宿主，显示出Breg活性。在拟议的研究中，我们将使用之前资助期开发的模型来描述Bregs对移植耐受的贡献。在Aim I中，我们将重点研究Breg抑制na¿ve Teff反应的机制，并检测Breg抗原特异性，表征Breg诱导的免疫反应特征变化，并定义免疫调节细胞因子（IL-10和TGF-?）的作用。在Aim II中，我们将利用我们的发现，即抗cd45rb诱导的耐受性依赖于Treg和B细胞，来探索Treg发育是由Bregs促进的，或者Tregs和Bregs合作促进移植物接受的可能性。最后，Aim III研究了共刺激分子TIM-1对抗cd45rb诱导的耐受性的贡献，并将依赖于我们的合作者Terry Strom博士生成的新的TIM1-/-线。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。

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.