Antigen Presentation in CD4-mediated Cardiac Rejection

CD4 介导的心脏排斥反应中的抗原呈递

• 批准号: 6692696
• 负责人: TODD J GRAZIA
• 金额: $ 5.63万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-03 至 2004-07-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6692696
• 关键词: MHC class II antigen; antigen presentation; bone marrow transplantation; cardiac myocytes; cytotoxic T lymphocyte; dendritic cells; gene targeting; genetically modified animals; heart transplantation; helper T lymphocyte; homologous transplantation; laboratory mouse; postdoctoral investigator; transplant rejection; vascular endothelium; whole body irradiation dosage

DESCRIPTION(provided by applicant): Solid organ transplantation remains the final common pathway for many end-stage diseases. However, mandatory non-specific immunosuppresion and acute rejection continue to result in significant morbidity and mortality. Our lab has thus far demonstrated that the CD4 T-cell is necessary and sufficient alone to illicit acute cardiac rejection. Additionally, we have shown that the 'direct' (donor-restricted) pathway is necessary for acute rejection whereas the 'indirect' (host-restricted) is not. A question that remains is which cell type is responsible for antigen presentation in 'direct' CD4-mediated acute cardiac rejection. We propose to answer this question by isolating antigen presentation to endothelial cells/cardiomyocytes or to dendritic cells by using bone marrow transplantation to create chimeric mice. As CD4-mediated rejection is is restricted by MHC class II expression, MHC class II knockout mice can be used as bone marrow recipients or donors, allowing isolation of MHC class II expression to the bone marrow-derived compartment or to the tissue-derived compartment (eg. endothelial cells). These chimeric mice can then serve as heart donors into immunodeficient recipients reconstituted with CD4 T-cells. Results of these studies will have significant implications for targeted therapy.

描述（由申请人提供）：固体器官移植仍然是许多终阶段疾病的最终共同途径。但是，强制性的非特异性免疫抑制和急性排斥反应继续导致显着的发病率和死亡率。迄今为止，我们的实验室表明，CD4 T细胞是必要的，并且足以单独进行非法急性心脏排斥。此外，我们已经表明，急性排斥的“直接”（供体限制）途径是必需的，而“间接”（宿主限制）不是。剩下的问题是，哪种细胞类型负责“直接” CD4介导的急性心脏排斥反应中的抗原表现。我们建议通过将抗原呈递分离为内皮细胞/心肌细胞或通过使用骨髓移植来产生嵌合小鼠来回答这个问题。由于CD4介导的排斥反应受到MHC II类表达的限制，因此MHC II类基因敲除小鼠可以用作骨髓受体或供体，从而可以将MHC II类表达分离为骨髓衍生的隔室或组织衍生的骨骼衍生的室室（例如，内皮细胞）。然后，这些嵌合小鼠可以用CD4 T细胞重组的免疫缺陷受体作为心脏供体。这些研究的结果将对靶向治疗产生重大影响。