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.

这一提议的中心假设是，控制CD 4 +25+调节性T细胞（Treg）的功能， 体内将消除对人凝血因子IX（hF.IX）抗原的细胞和体液免疫应答， 其通过腺相关病毒（rAAV）基因转移施用。因为Treg细胞的标记物 最近才变得可用，现在有可能增加体内活化Treg细胞的数量。 本申请中提出的实验旨在检查以下方法的贡献和局限性 基于Treg细胞抑制的GITR和GITR-配体对由rAAV-hF.IX基因转移引起的细胞介导的和体液免疫应答的开关。其次，将应用基于Treg细胞的过继转移的细胞疗法来控制rAAV-hF.IX诱导的细胞介导的应答。第三，将从移植领域调整一种针对活化的致细胞病变反应性T细胞和备用免疫调节网络的策略。 本申请中提出的实验按以下具体目标分组： 具体目的#1：为了检验施用可溶性GITR-配体-Fc融合蛋白[Fc-Fc]对小鼠的免疫应答的假设， GITR-L]使Treg细胞功能失活，从而增强对rAAV-hF的体液和细胞免疫应答。 九. 具体目标#2：为了检验用针对小鼠GITR-L的单克隆抗体处理增强Treg细胞抑制和对hF.IX抗原和AAV衣壳抗原的免疫耐受性的假设。 具体目标#3：为了检验潜在致病性T细胞的抑制和/或缺失促进Treg介导的对hF. IX的免疫耐受的假设。 总之，这些实验应该阐明Treg细胞控制的途径在rAAV hF.IX基因中的作用。 疗法这些研究的结果应该提出可以立即应用的治疗策略 对血友病患者来说。