IMMUNE

这一建议的中心假设是控制CD4+25+调节性T细胞(Treg)的功能。 Vivo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)基因转移给药。因为Treg细胞的标记物 直到最近才有可能增加体内激活的Treg细胞的数量。 本申请中提出的实验旨在检验 基于Treg细胞开关的GITR和GITR-Ligand抑制rAAV-hF.IX基因转移诱导的细胞和体液免疫反应。其次，以Treg细胞为基础的过继转移细胞疗法将被用于控制rAAV-hF.IX诱导的细胞介导的反应。第三，移植领域将采用一种针对激活的细胞病变反应性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： 具体目标#1：测试注射可溶性GITR-Ligand-Fc融合蛋白[Fc- L]灭活Treg细胞功能，从而增强对rAAV-HF的体液和细胞免疫反应。 IX. 特定目的#2：验证针对小鼠GITR-L的单抗治疗增强Treg细胞抑制和对hF.IX抗原和甲型肝炎病毒衣壳抗原的免疫耐受性的假设。 具体目标#3：验证潜在致病T细胞的抑制和/或缺失有助于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rAAV hF.IX基因中Treg细胞控制的通路的作用 心理治疗。这些研究的结果应该提出可以立即应用的治疗策略。 血友病患者。

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.