Immunotherapy of Adenovirus Infections in Stem Cell Transplnt Recipients

这项提案的目标是确定潜在的免疫治疗靶点，用于治疗红斑狼疮 接受异基因干细胞移植的癌症患者中的腺病毒病。虽然 腺病毒可导致干细胞移植后的致命感染，目前还没有既定的治疗方法。 基于成功使用供体淋巴细胞输注治疗其他病毒感染，如 EB病毒，我们建议T细胞免疫疗法可能有助于控制腺病毒病 移植后。我们的实验室是第一个记录腺病毒特异性记忆CD4+和CD8+T细胞的实验室 大多数健康成人外周血中的细胞反应。我们已经确认了六角体是 免疫优势衣壳蛋白靶标，包含不同物种间高度保守的表位 腺病毒血清型。然而，目前尚不清楚是否只有六邻体特异性T细胞反应 足以控制急性感染。我们假设，在体内，T细胞的靶向是调节 在感染细胞中早期表达的腺病毒蛋白可能比Hexon特异性J更有效 细胞，因为它们将1)在病毒复制之前消除受感染的细胞，2)在病毒复制之前识别细胞 对腺病毒319K介导的MHC类L限制性抗原提呈的抑制作用。我们 建议通过对记忆腺病毒特异性T细胞的分析来确定主要的早期蛋白质靶点 健康成人对个别蛋白质和合成肽的反应。另外， 急性白血病干细胞移植受者的病毒特异性T细胞应答模式 腺病毒感染将通过干扰素-γELISPOT、细胞因子流式细胞术和细胞毒性T细胞测定进行评估 细胞分析，并与临床结果相关。这些研究将提供工具和科学 为将来治疗腺病毒疾病的免疫疗法试验奠定了基础。预计 这项工作将提高接受干细胞移植的患者的存活率。

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 viralreplication and 2) recognize cells prior to adenovirus ¿3 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-y 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.