ADJUNCT IMMUNOTHERAPY FOR ADENOVIRAL GENE THERAPY

描述（直接取自应用程序） 使用重组腺病毒载体治疗慢性阻塞性肺疾病 囊性纤维化已经被所产生的免疫反应所阻碍， 载体的宿主和载体转导的细胞。 普通长期 使用标准试剂如环孢菌素的免疫抑制疗法已经 在抑制免疫介导的表达清除方面没有成功。 虽然使用细胞消融疗法已经取得了一些成功，但这 这种方法导致全身副作用，并且广泛地具有免疫抑制作用。 我们已经在改变宿主反应方面取得了部分成功 通过选择性地阻断 T淋巴细胞和抗原呈递细胞（APC）上的共刺激配体， 在启动有效的。 抗原特异性的 免疫反应。 共刺激阻断 使用可溶性免疫球蛋白检测T细胞上的CD 28与APC上的B7-1，-2之间的相互作用 CTLA 4 Ig和APC上的CD 40与T细胞上的配体的相互作用 使用抗CD 40配体mAb具有几个潜在的优点， 细胞清除疗法：（1）它导致短暂的免疫抑制，（2）它 不是细胞消融性的并且不影响其它细胞（例如，中性粒细胞） 参与先天免疫反应。 (3)它对 （1）免疫原性;（2）免疫原性不太可能导致 对野生型腺病毒的耐受性。 我们计划使用我们的 初步研究作为一个起点，以确定这些 代理，可以安全地规避免疫介导的限制， 腺病毒介导的基因治疗。 具体来说，我们计划研究 肝脏和肺部基因表达的持续性，以及宿主 对接受第一代或第二代的小鼠的免疫应答 具有或不具有可溶性或载体的组合的腺病毒载体 表达CTLA 4 Ig/抗2CD 40配体。 这些研究应该揭示重要的 关于使用重组腺病毒载体用于 囊性纤维化的基因治疗

DESCRIPTION (Taken directly from the application) The excitement of using recombinant adenovirus vectors for the treatment of cystic fibrosis has been hindered by the resulting immunologic response of the host to the vector and vector transduced cells. General long-term immunosuppressive therapy using standard agents, such as cyclosporin, have not been successful in inhibiting immune mediated clearance of expression. Although some success has been achieved using cytoablative therapy, this approach results in systemic-side effects and is broadly immunosuppressive. We have sought and obtained partial success in modifying the host response to enhance gene expression, by selectively blocking the interactions of costimulatory ligands on T lymphocytes and antigen presenting cells (APC), which play an important role in the initiation of an effective. antigen-specific. immunologic response. Blockade of the costimulatory interactions between CD28 on T cells with B7-1,-2 on APC using soluble CTLA4Ig and of the interaction of CD40 on APC with its ligand on T cells using anti-CD40 ligand mAb has several potential advantages over cytoablative therapy: (l) it results in transient immunosuppression, (2) it is not cytoablative and does not affect other cells (e.g., neutrophils) involved in innate immune responses. (3) it has minimal effect on pre-existing immunity and (4) it is unlikely to result in immunological tolerance to wild type adenovirus. We plan to use the results from our initial studies as a starting point to determine whether or not these agents, can safely circumvent immune-mediated limitations to adenoviral-mediated gene therapy. Specifically, we plan to study persistence of liver and pulmonary gene expression, and the host immunological response to mice receiving either first or advanced generation adenovirus vectors with or without combinations of soluble or vector expressed CTLA4Ig/ anti2CD40 ligand. These studies should reveal important information as to the future of using recombinant adenovirus vectors for gene therapy for cystic fibrosis.