Mechanisms of B Cell-Dependent Transplantation Tolerance

描述(由申请人提供)：对自身抗原和外来病原体的免疫反应的调节是宿主生存所不可或缺的。所涉及的自然调节途径可能也提供了干预不良免疫反应的机会，例如发生在同种异体移植中的免疫反应。这种方法的吸引力明显体现在人们对应用调节性T细胞(Tregs)来促进患者移植存活的热情上。最近的证据表明，免疫反应的体液臂中可能存在平行的调控途径，尽管涉及的确切细胞和调控机制尚未完全确定。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、传染病和骨髓移植/GVHD)中的作用，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很好的证实。在上一次资助期间，我们出人意料地观察到，抗体诱导的移植耐受模型依赖于B淋巴细胞的存在，并且该模型中移植物的延长可以通过Tim-1+B细胞转移到第二宿主，显示出Breg活性。在拟议的研究中，我们将使用前一个资助期开发的模型来表征Bregs对移植耐受的贡献。在目标I中，我们重点研究Bregs抑制幼稚T细胞应答的机制，检测BREG抗原的特异性，描述Bregs诱导的免疫应答特征的变化，并确定免疫调节细胞因子(IL-10和转化生长因子β)的作用。在AIM II中，我们将利用我们的发现，即抗CD45RB诱导的耐受依赖于Tregs和B细胞，以探索Treg发育是由Bregs促进的，或者Tregs和Bregs合作促进移植接受。最后，AIM III研究了共刺激分子TIM-1在抗CD45RB诱导的耐受中的作用，并将依赖于我们的合作者Terry Strom博士产生的新的TIM1-/-线。总的来说，这些研究将进一步加深我们对调节性B细胞在移植耐受中的独特贡献的理解。

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 naïve 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-ß). 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.