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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要/摘要同种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。 B细胞衍生的同种抗体是在此响应中生成的有助于感染控制，但构成了挽救生命输血或移植的障碍。最突出的同种异体体液障碍是MHC I类人白细胞抗原（HLA）强烈的免疫原性和广泛的组织表达。这些抗原的供体特异性抗体处于领先地位抗体介导的移植物排斥和无效血小板输血的原因。靶向HLA特异性抗体 - 产生B细胞，我们通过将HLA I类抗原与FC联系起来设计了MHC-FC融合蛋白抗体分子的一部分。我们的初步数据表明，这种HLA I类I-FC融合蛋白有力地杀死 B细胞杂交瘤具有同源特异性。这种效果以抗原特异性和FC依赖性方式发生体外和体内。在这里，我们将扩展我们的发现，以检查在临床前环境中的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过程并减弱对特定MHC I类抗原的同种异体免疫化。我们将检验这个中心假设在三个目标中。在AIM 1中，我们将评估血小板中MHC-FC治疗的功效和特异性磨性模型。在AIM 2中，我们将通过MHC-FC治疗在皮肤中测试脱敏的可行性移植模型。在AIM 3中，我们将测试MHC-FC治疗是否可以诱导抗原特异性体液在涉及骨FIDE多克隆B细胞的鼠类同种免疫模型中的抑制作用，产生抗MHC类我抗体。我们提出的工作允许对模型的模型中的MHC-FC原型进行批判性评估其预期的临床应用（目标1和2）的设置，或提供B细胞的生理来源治疗靶标（目标3）。这些实验的结果将精确地开辟一条新的研究途径选择性诱导抗原特异性体液耐受性的药物。