Immunotherapy of Adenovirus Infections in Stem Cell Transplant Recipients

干细胞移植受者腺病毒感染的免疫治疗

• 批准号: 7167150
• 负责人: PHYLLIS Rudolph FLOMENBERG
• 金额: $ 30.3万
• 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/7167150
• 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; Interferons; 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; 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

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.

描述（由申请人提供）：本提案的目的是确定接受同种异体干细胞移植的癌症患者中腺病毒疾病治疗的潜在免疫靶点。虽然腺病毒可以在干细胞移植后引起致命的感染，但目前还没有确定的治疗方法。基于供体淋巴细胞输注治疗其他病毒感染（如Epstein巴尔病毒）的成功应用，我们提出T细胞免疫疗法可能有助于控制移植后腺病毒疾病。我们的实验室是第一个记录腺病毒特异性记忆CD 4+和CD 8 + T细胞反应在外周血从大多数健康成人。我们已经确定了六邻体作为免疫显性衣壳蛋白的目标，含有不同的腺病毒血清型之间高度保守的表位。然而，尚不清楚单独的六邻体特异性T细胞应答是否足以控制急性感染。我们假设，在体内，靶向受感染细胞中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受感染的细胞和2）在腺病毒E3 19 k介导的MHC I类限制性抗原呈递抑制之前识别细胞。我们建议通过分析健康成年人对单个蛋白质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，病毒特异性T细胞反应的干细胞移植受者谁开发急性腺病毒感染的模式将评估IFN-？ELISPOT、细胞因子流式细胞术和细胞毒性T细胞测定并与临床结果相关。这些研究将为未来腺病毒疾病的免疫治疗试验提供工具和科学依据。预计这项工作将改善接受干细胞移植的患者的生存率。