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:
    10612453
  • 负责人:
  • 金额:
    $ 19.5万
  • 依托单位:
  • 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 2025-03-31
  • 项目状态:
    未结题

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.
项目总结/文摘

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Antigen-guided depletion of anti-HLA antibody-producing cells by HLA-Fc fusion proteins.
通过 HLA-Fc 融合蛋白抗原引导消除抗 HLA 抗体产生细胞。
  • DOI:
    10.1182/blood.2022016376
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    20.3
  • 作者:
    Webber,AshleeM;Bradstreet,TaraR;Wang,Xiaoli;Guo,Hongjie;Nelson,ChristopherA;Fremont,DavedH;Edelson,BrianT;Liu,Chang
  • 通讯作者:
    Liu,Chang
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Brian Todd Edelson其他文献

Brian Todd Edelson的其他文献

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{{ truncateString('Brian Todd Edelson', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 19.5万
  • 项目类别:
Role of Intestinal Parasites on Regulating Immune Responses to Gut Antigens
肠道寄生虫在调节肠道抗原免疫反应中的作用
  • 批准号:
    10445670
  • 财政年份:
    2022
  • 资助金额:
    $ 19.5万
  • 项目类别:
Role of Intestinal Parasites on Regulating Immune Responses to Gut Antigens
肠道寄生虫在调节肠道抗原免疫反应中的作用
  • 批准号:
    10651714
  • 财政年份:
    2022
  • 资助金额:
    $ 19.5万
  • 项目类别:
Immunologic Characterization of CSF microglia in multiple sclerosis
多发性硬化症脑脊液小胶质细胞的免疫学特征
  • 批准号:
    10196298
  • 财政年份:
    2021
  • 资助金额:
    $ 19.5万
  • 项目类别:
Immunologic Characterization of CSF microglia in multiple sclerosis
多发性硬化症脑脊液小胶质细胞的免疫学特征
  • 批准号:
    10374170
  • 财政年份:
    2021
  • 资助金额:
    $ 19.5万
  • 项目类别:
Regulation of Immune Responses to Mycobacterium tuberculosis Infection
结核分枝杆菌感染免疫反应的调节
  • 批准号:
    10465067
  • 财政年份:
    2018
  • 资助金额:
    $ 19.5万
  • 项目类别:
Regulation of Immune Responses to Mycobacterium tuberculosis Infection
结核分枝杆菌感染免疫反应的调节
  • 批准号:
    10231224
  • 财政年份:
    2018
  • 资助金额:
    $ 19.5万
  • 项目类别:
Regulation of Immune Responses to Mycobacterium tuberculosis Infection
结核分枝杆菌感染免疫反应的调节
  • 批准号:
    9789818
  • 财政年份:
    2018
  • 资助金额:
    $ 19.5万
  • 项目类别:
UNDERSTANDING AUTOREACTIVE T CELL PATHOGENICITY
了解自身反应性 T 细胞致病性
  • 批准号:
    9247751
  • 财政年份:
    2015
  • 资助金额:
    $ 19.5万
  • 项目类别:
UNDERSTANDING AUTOREACTIVE T CELL PATHOGENICITY
了解自身反应性 T 细胞致病性
  • 批准号:
    8835343
  • 财政年份:
    2015
  • 资助金额:
    $ 19.5万
  • 项目类别:

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