Immunotherapy of Adenovirus Infections in Stem Cell Transplant Recipients

描述(申请人提供)：这项提案的目标是确定潜在的免疫治疗靶点，用于治疗接受异基因干细胞移植的癌症患者的腺病毒疾病。虽然腺病毒可以导致干细胞移植后的致命感染，但目前还没有既定的治疗方法。基于供者淋巴细胞输注治疗其他病毒感染(如EB病毒)的成功经验，我们认为T细胞免疫疗法可能有助于控制移植后的腺病毒病。我们的实验室首次在大多数健康成年人的外周血中记录腺病毒特异性记忆CD4和CD8 T细胞反应。我们已经确定六邻体是免疫优势衣壳蛋白的靶标，包含在不同的腺病毒血清型之间高度保守的表位。然而，目前尚不清楚仅有六邻体特异性T细胞反应是否足以控制急性感染。我们推测，在体内，靶向感染细胞早期表达的调节性腺病毒蛋白的T细胞可能比六邻体特异性J细胞更有效，因为它们将1)在病毒复制之前消除感染细胞，2)在腺病毒E319K介导的抑制MHC类L限制性抗原递呈之前识别细胞。我们建议通过分析健康成年人对单个蛋白和合成肽的记忆腺病毒特异性T细胞反应来确定主要的早期蛋白质靶点。此外，发生急性腺病毒感染的干细胞移植受者的病毒特异性T细胞反应模式将通过干扰素？ELISPOT、细胞因子流式细胞术和细胞毒性T细胞检测，并与临床结果相关。这些研究将为未来腺病毒病的免疫治疗试验提供工具和科学依据。预计这项工作将提高接受干细胞移植的患者的存活率。

DESCRIPTION (provided by applicant): The goal of this proposal is to identify potential immunotherapeutic targets for treatment of adenovirus disease in cancer patients who receive allogeneic stem cell transplants. Although adenoviruses can cause fatal infections post- stem cell transplant, there is no established therapy. Based on the successful use of donor lymphocyte infusions to treat other viral infections such as Epstein Barr virus, we propose that T cell immunotherapy may help control adenovirus disease post-transplant. Our lab was the first to document adenovirus -specific memory CD4+ and CD8+ T cell responses in peripheral blood from most healthy adults. We have identified hexon as the immunodominant capsid protein target, containing epitopes highly conserved among different adenovirus serotypes. However, it is not known whether hexon-specific T cell responses alone are adequate to control acute infection. We hypothesize that, in vivo, T cells targeted to regulatory adenovirus proteins expressed early in infected cells may be more efficient than hexon-specific J cells because they will 1) eliminate infected cells prior to viral replication and 2) recognize cells prior to adenovirus E3 19k-mediated inhibition of MHC class l-restricted antigen presentation. We propose to identify major early protein targets by analysis of memory adenovirus-specific T cell responses in healthy adults against individual proteins and synthetic peptides. Additionally, patterns of virus-specific T cell responses in stem cell transplant recipients who develop acute adenovirus infections will be evaluated by IFN-? ELISPOT, cytokine flow cytometry, and cytotoxic T cell assays and correlated with clinical outcomes. These studies will provide the tools and scientific basis for a future immunotherapy trial for the treatment of adenovirus disease. It is anticipated that this work will lead to an improvement in the survival of patients who undergo stem cell transplants.