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

项目摘要/摘要 同种异体免疫是宿主在怀孕期间遇到的同种异体抗原的生理反应， 输血，或移植。在这种反应中会产生B细胞衍生的同种异体抗体，而不是 有助于控制感染，但却构成了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类人类白细胞抗原(HLA)，因为它们 免疫原性强，组织表达广泛。针对这些抗原的供体特异性抗体是主要的 抗体介导的移植物排斥反应和血小板输注无效的原因。靶向人类白细胞抗原特异性抗体- 为了生产B细胞，我们通过将HLAI类抗原与Fc连接起来，设计出了MHC-Fc融合蛋白 抗体分子的一部分。我们的初步数据显示，这种HLAI-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。这种效应是以抗原特异性和Fc依赖的方式发生的 在体外和体内。在这里，我们将扩展我们的发现，在临床前环境中检查这些铅生物制剂，以 演示它们的适用性。我们假设MHC-FC治疗可以改变抗体介导的疾病 处理并减弱对特定MHC I类抗原的同种异体免疫。我们将检验这一中心假设 有三个目标。在目标1中，我们将评估MHC-FC治疗血小板的有效性和特异性。 耐火性模型。在目标2中，我们将在皮肤上测试MHC-FC治疗脱敏的可行性 移植模型。在目标3中，我们将测试MHC-FC处理是否能诱导抗原特异性体液 骨多克隆B细胞产生抗MHC类抗体的小鼠同种异体免疫模型的抑制作用 我的抗体。我们建议的工作允许在模拟MHC-FC原型的模型中对MHC-FC原型进行关键评估 他们预期的临床应用的环境(目标1和2)或提供B细胞的生理来源作为 治疗靶点(目标3)。这些实验的结果将为精密研究开辟一条新的途径。 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.