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

MHC-Fc 融合蛋白选择性诱导同种异体抗原特异性体液耐受

• 批准号: 10432434
• 负责人: Brian Todd Edelson
• 金额: $ 23.63万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-21 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432434
• 关键词: Alloantigen; Allogenic; Alloimmunization; Antibodies; Antibody-Producing Cells; Antigen Targeting; Antigens; Attenuated; B-Lymphocytes; Biological Products; Blood Platelets; Blood Transfusion; Chimeric Proteins; Data; Disease; Engineering; Evaluation; Goals; Graft Rejection; HLA Antigens; Haplotypes; Histocompatibility Antigens Class I; Human; Humoral Immunities; Hybridomas; Immune response; Immunize; Immunodeficient Mouse; Immunoglobulin-Secreting Cells; Immunosuppression; In Vitro; Inbred BALB C Mice; Infection Control; Isoantibodies; Lead; Life; MHC Class I Genes; Mediating; Memory B-Lymphocyte; Modeling; Monitor; Monoclonal Antibodies; Mus; Organ Transplantation; Outcome; Physiological; Plasma Cells; Platelet Transfusion; Pregnancy; Process; Proteins; Refractory; Research; Savings; Serology; Skin; Skin Transplantation; Source; Specificity; Splenocyte; Structure of germinal center of lymph node; Testing; Tissues; Transfusion; Transgenic Mice; Transplantation; Work; bone; clinical application; clinically relevant; desensitization; donor-specific antibody; efficacy evaluation; experimental study; feasibility testing; immunogenicity; improved; in vivo; infection risk; link protein; mouse model; novel; novel strategies; pre-clinical; precision medicine; prototype; response; therapeutic target; therapy development; transplant model

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.

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，此类HLA I-Fc融合蛋白具有强效杀伤作用 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铅生物制剂， 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。