Immunotherapy of Adenovirus Infections in Stem Cell Transplnt Recipients

干细胞移植受体中腺病毒感染的免疫治疗

• 批准号: 7337161
• 负责人: PHYLLIS Rudolph FLOMENBERG
• 金额: $ 29.72万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337161
• 关键词: Acute; Adenovirus Infections; Adenovirus Protein; Adenoviruses; Adult; Age; Allogenic; Antigen Presentation; Antigens; Biological Assay; CD8B1 gene; Cancer Patient; Capsid Proteins; Cells; Class; Clinical; Clinical Treatment; Clinical Trials; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Disease; Donor Lymphocyte Infusion; Epitopes; Flow Cytometry; Frequencies; Future; General Population; Goals; Histocompatibility Antigens Class II; Human Herpesvirus 4; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Lead; Mediating; Memory; Messenger RNA; Morbidity - disease rate; Outcome; Patients; Pattern; Peptides; Play; Proteins; Rate; Recovery; Research Personnel; Risk Factors; Role; Serotyping; Specificity; Stem cell transplant; Stem cells; T memory cell; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Epitopes; Transplant Recipients; Viral; Virus; Virus Diseases; Work; adult stem cell; base; cytokine; enzyme linked immunospot assay; graft vs host disease; improved; in vivo; mortality; peripheral blood; post-transplant disease; programs; reconstitution; response; synthetic peptide; tool

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.

该提案的目标是确定治疗以下疾病的潜在免疫治疗靶点： 接受同种异体干细胞移植的癌症患者的腺病毒病。虽然 腺病毒可导致干细胞移植后致命的感染，目前尚无成熟的治疗方法。 基于成功使用供体淋巴细胞输注治疗其他​​病毒感染，例如 Epstein Barr病毒，我们提出T细胞免疫疗法可能有助于控制腺病毒疾病 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的实验室 大多数健康成年人外周血中的细胞反应。我们已经将六邻体确定为 免疫显性衣壳蛋白靶标，含有不同种间高度保守的表位 腺病毒血清型。然而，尚不清楚六邻体特异性 T 细胞反应是否单独有效。 足以控制急性感染。我们假设，在体内，T 细胞靶向调节 在感染细胞中早期表达的腺病毒蛋白可能比六邻体特异性 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 腺病毒 ¿3 19k 介导的 MHC L 类限制性抗原呈递抑制。我们 提议通过分析记忆腺病毒特异性 T 细胞来识别主要的早期蛋白质靶标 健康成年人对单个蛋白质和合成肽的反应。此外， 干细胞移植受者发生急性发作时的病毒特异性 T 细胞反应模式 腺病毒感染将通过 IFN-y ELISPOT、细胞因子流式细胞术和细胞毒性 T 进行评估 细胞测定并与临床结果相关。这些研究将提供工具和科学 为未来治疗腺病毒疾病的免疫疗法试验奠定基础。预计 这项工作将改善接受干细胞移植的患者的生存率。