IMMUNE

免疫

• 批准号: 7885362
• 负责人: CORNELIS P TERHORST
• 金额: $ 35.49万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885362
• 关键词: Adoptive Transfer; Antigens; Capsid; Cell Therapy; Cell physiology; Cells; Chimeric Proteins; Factor IX; Gene Transfer; Hemophilia A; Human; Immune; Immune Tolerance; Immune response; Ligands; Mediating; Monoclonal Antibodies; Mus; Pathway interactions; Patients; Role; T-Lymphocyte; Testing; Therapeutic; Transplantation; Viral; base; design; gene therapy; in vivo; research study; response

The central hypothesis of this proposal is that controlling the function of CD4+25+ reguhatory T cells (Treg) in vivo will abrogate cellular and humoral immune responses to human coagulation factor IX (hF.IX) antigen, which is administered by adeno-associated viral (rAAV) gene transfer. Because markers of Treg cells have only recently become available, it is now possible to enhance the number of activated Treg cells in vivo. The experiments proposed in this application are designed to examine the contributions and limitations of GITR and GITR-Ligand based on/off switches of Treg cell suppression of cell-mediated and humoral immune responses elicited by rAAV-hF.IX gene transfer. Secondly, adoptive transfer based cell therapy with Treg cells will be applied to control the rAAV-hF.IX induced cell-mediated responses. Third a strategy that targets activated cytopathic reactive T cells and spares immunoregulatory networks will be adapted from the transplantation field. The experiments proposed in this application are grouped in the following specific aims: Specific Aim #1: To test the hypothesis that administering a soluble GITR-Ligand-Fc fusion protein [Fc- GITR-L] inactivates Treg cell functions and thus enhances humoral and cellular immune responses to rAAV-hF. IX. Specific Aim #2: To test the hypothesis that treatment with a monoclonal antibody directed at mouse GITR-L enhances Treg cell suppression and immune tolerance to hF.IX antigens and AAV capsid antigen. Specific Aim #3: To test the hypothesis that suppression and/or deletion of potentially pathogenic T cells facilitates Treg mediated immunologic tolerance towards hF.IX.. Together these experiments should clarify the role of Treg cell controlled pathways in rAAV hF.IX gene therapy. The results of these studies should suggest therapeutic strategies that can immediately be applied to hemophilia patients.

该提议的中心假设是控制CD4+ 25+校长T细胞（Treg）在 体内将消除对人类凝血因子IX（HF.IX）抗原的细胞和体液免疫反应， 通过腺相关病毒（RAAV）基因转移来给药。因为Treg细胞的标记具有 直到最近才能可用，现在才有可能在体内增加活化的Treg细胞的数量。 本应用程序中提出的实验旨在检查 GITR和GITR - 配体基于/OFF/OFF开关的TREG细胞抑制细胞介导的和体液免疫反应，由RAAV-HF.IX基因转移引起。其次，将基于Treg细胞的基于收养的细胞治疗将用于控制RAAV-HF.IX诱导的细胞介导的反应。第三，针对激活的细胞病毒反应性T细胞和备用免疫调节网络的策略将从移植场进行调整。 本应用程序中提出的实验分组以下特定目的： 特定目的＃1：检验以下假设，即管理可溶性GITR-er-gand-fc融合蛋白[FC- gitr-l]灭活Treg细胞功能，从而增强了对RAAV-HF的体液和细胞免疫反应。 ix。 具体目的＃2：测试以小鼠gitr-l的单克隆抗体治疗的假设可增强对hf.ix抗原和AAV capsid抗原的Treg细胞抑制和免疫耐受性。 具体目的3：检验以下假设：抑制和/或缺失潜在的病原T细胞促进了Treg介导的对HF.IX的免疫耐受性。 这些实验应阐明Treg细胞控制途径在RAAV HF.IX基因中的作用 治疗。这些研究的结果应提出可以立即应用的治疗策略 对血友病患者。