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
- 来源:
- 关键词:AlloantigenAllogenicAlloimmunizationAntibodiesAntibody-Producing CellsAntigen TargetingAntigensAttenuatedB-LymphocytesBiological ProductsBlood PlateletsBlood TransfusionChimeric ProteinsDataDiseaseEngineeringEvaluationGoalsGraft RejectionHLA AntigensHaplotypesHistocompatibility Antigens Class IHumanHumoral ImmunitiesHybridomasI-antigenImmune responseImmunizeImmunodeficient MouseImmunoglobulin-Secreting CellsImmunosuppressionIn VitroInbred BALB C MiceInfection ControlIsoantibodiesLeadLifeMHC Class I GenesMediatingMemory B-LymphocyteModelingMonitorMonoclonal AntibodiesMusOrgan TransplantationOutcomePhysiologicalPlasma CellsPlatelet TransfusionPregnancyProcessProteinsRefractoryResearchSerologySkinSkin TransplantationSourceSpecificitySplenocyteStructure of germinal center of lymph nodeTestingTissuesTransfusionTransgenic MiceTransplantationWorkboneclinical applicationclinically relevantdesensitizationdonor-specific antibodyefficacy evaluationexperimental studyfeasibility testingimmunogenicityimprovedin vivoinfection risklink proteinmouse modelnovelnovel strategiespre-clinicalprecision medicineprototyperesponsetherapeutic targettherapy developmenttransplant model
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
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10651714 - 财政年份:2022
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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
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10196298 - 财政年份:2021
- 资助金额:
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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
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- 资助金额:
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Regulation of Immune Responses to Mycobacterium tuberculosis Infection
结核分枝杆菌感染免疫反应的调节
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10465067 - 财政年份:2018
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Regulation of Immune Responses to Mycobacterium tuberculosis Infection
结核分枝杆菌感染免疫反应的调节
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10231224 - 财政年份:2018
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Regulation of Immune Responses to Mycobacterium tuberculosis Infection
结核分枝杆菌感染免疫反应的调节
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9789818 - 财政年份:2018
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$ 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
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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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