ADJUNCT IMMUNOTHERAPY FOR ADENOVIRAL GENE THERAPY

腺病毒基因治疗的辅助免疫治疗

• 批准号: 2905928
• 负责人: Mark A Kay
• 金额: $ 24.77万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2905928
• 关键词: Adenoviridae; cystic fibrosis; gene therapy; immunotherapy; laboratory mouse; nonhuman therapy evaluation; tissue /cell culture

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.

描述(直接从应用程序中获取) 重组腺病毒载体治疗慢性粒细胞白血病的兴奋性 囊性纤维化被由此产生的免疫反应所阻碍 宿主载体和载体转导细胞。一般长期 使用标准药物的免疫抑制疗法，如环孢素，有 在抑制免疫介导的表达清除方面未获成功。 虽然使用细胞切除疗法已经取得了一些成功，但这 该方法会导致全身副作用，并具有广泛的免疫抑制作用。 我们已经在修改宿主响应方面取得了部分成功 通过选择性地阻断基因的相互作用来增强基因表达 T淋巴细胞和抗原提呈细胞(APC)上的共刺激配体， 它们在有效的启动中起着重要的作用。 抗原特异型。免疫反应。对共刺激的封锁 可溶性T细胞表面CD28与APC表面B7-1、B7-2的相互作用 CTLA4Ig及APC表面CD40与T细胞表面配体相互作用的研究 使用抗CD40配体单抗具有几个潜在的优点 细胞剥离治疗：(L)它导致一过性免疫抑制，(2)它 不具有细胞去除性，不影响其他细胞(如中性粒细胞) 参与先天免疫反应。(3)对……的影响很小 预先存在的免疫和(4)它不太可能导致免疫性 对野生型腺病毒的耐受。我们计划使用来自我们的 以初步研究为起点来确定这些 代理，可以安全地绕过免疫介导的限制 腺病毒介导的基因治疗。具体地说，我们计划研究 持续的肝和肺基因表达，以及宿主 第一代或高级代小鼠的免疫学反应 带有或不带有可溶性或载体组合的腺病毒载体 表达CTLA4Ig/抗2CD40配体。这些研究应该揭示出重要的 关于重组腺病毒载体用于治疗的未来的信息 囊性纤维化的基因治疗。