Selective induction of alloantigen-specific humoral tolerance by MHC-Fc fusion proteins

项目总结/摘要 同种免疫是宿主在妊娠期间遇到同种抗原的生理反应， 输血或移植。在这种应答中产生B细胞衍生的同种抗体， 有助于感染控制，但反而构成了对挽救生命的输血或移植的障碍。 最突出的同种异体体液屏障是MHC I类人白细胞抗原（HLA），这是由于它们的免疫原性。 免疫原性强、组织表达广。针对这些抗原的供体特异性抗体 抗体介导的移植排斥和无效血小板输注的原因。针对HLA特异性抗体- 为了生产B细胞，我们通过将HLA-I类抗原与Fc 抗体分子的一部分。我们的初步数据表明，这种HLA I类-Fc融合蛋白可以有效地杀死 具有同源特异性的B细胞杂交瘤。这种作用以抗原特异性和Fc依赖性方式发生 在体外和体内。在这里，我们将扩展我们的研究结果，在临床前环境中检查这些主要生物制剂， 证明其适用性。我们假设MHC-Fc治疗可以改变抗体介导的疾病， 处理并减弱对特异性MHC I类抗原的同种免疫。我们将检验这一中心假设 三个目标。在目标1中，我们将评估MHC-Fc治疗血小板减少性紫癜的疗效和特异性。 耐火度模型在目标2中，我们将测试通过MHC-Fc治疗皮肤中的脱敏的可行性。 移植模型在目标3中，我们将测试MHC-Fc处理是否可以诱导抗原特异性体液免疫。 在涉及产生抗MHC类抗体的骨髓多克隆B细胞的鼠同种异体免疫模型中的抑制 I抗体。我们提出的工作允许在模型中对MHC-Fc原型进行关键评估， 或提供B细胞的生理来源作为其预期的临床应用（目的1和2）的环境。 治疗目标（Aim 3）。这些实验的结果将为精密度的研究开辟一条新的途径 用于选择性诱导抗原特异性体液耐受的药物。

PROJECT SUMMARY/ABSTRACT Alloimmunization is the physiological response to allogeneic antigens encountered by the host during pregnancy, blood transfusion, or transplantation. B cell-derived alloantibodies are generated in this response which do not contribute to infection control but instead constitute a barrier to life-saving blood transfusion or transplantation. The most prominent allogeneic humoral barriers are MHC class I human leukocyte antigens (HLA) due to their strong immunogenicity and broad tissue expression. Donor-specific antibodies to these antigens are leading causes of antibody-mediated graft rejection and ineffective platelet transfusion. To target HLA-specific antibody- producing B cells, we have engineered MHC-Fc fusion proteins by linking an HLA class I antigen with the Fc portion of an antibody molecule. Our preliminary data show that such HLA class I-Fc fusion proteins potently kill B cell hybridomas with cognate specificities. This effect occurs in an antigen-specific and Fc-dependent manner in vitro and in vivo. Here, we will extend our findings to examine these lead biologics in pre-clinical settings to demonstrate their applicability. We hypothesize that MHC-Fc treatment can modify antibody-mediated disease processes and attenuate alloimmunization to specific MHC class I antigens. We will test this central hypothesis in three aims. In Aim 1, we will evaluate the efficacy and specificity of MHC-Fc treatment in a platelet refractoriness model. In Aim 2, we will test the feasibility of desensitization by MHC-Fc treatment in a skin transplant model. In Aim 3, we will test whether MHC-Fc treatment can induce antigen-specific humoral suppression in a murine alloimmunization model involving bone fide polyclonal B cells producing anti-MHC class I antibodies. Our proposed work allows critical evaluation of MHC-Fc prototypes in models that either mimic the settings of their anticipated clinical applications (Aims 1 and 2) or offer a physiological source of B cells as the therapeutic target (Aim 3). The results from these experiments will open a novel avenue of research in precision medicine for the selective induction of antigen-specific humoral tolerance.