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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

基本信息

批准号：
7545814
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
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7545814
关键词：
Acute Adenovirus Infections Adenovirus Protein Adenoviruses Adult Age Allogenic Antigen Presentation Antigens Biological Assay CD8B1 gene Cancer Patient Capsid Proteins Cells 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 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 comparative efficacy cytokine enzyme linked immunospot assay graft vs host disease improved in vivo mortality peripheral blood post-transplant disease programs reconstitution response synthetic peptide tool

项目摘要

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潜在的免疫靶点，用于治疗接受异基因干细胞移植的癌症患者中的腺病毒疾病。虽然腺病毒可导致干细胞移植后的致命感染，目前还没有确定的治疗方法。基于供体淋巴细胞输注成功用于治疗其他病毒感染，爱泼斯坦巴尔病毒，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。我们已经确定六邻体是免疫显性衣壳蛋白靶向，含有在不同腺病毒血清型。然而，尚不清楚单独的六邻体特异性T细胞应答是否是免疫应答。足以控制急性感染。我们假设，在体内，靶向调节性T细胞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 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319 k介导的MHC I类限制性抗原呈递的抑制。我们建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靶点在健康成人对个别蛋白质和合成肽的反应。此外，本发明还发生急性白血病的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IFN-γ ELISPOT、细胞因子流式细胞术和细胞毒性T细胞分析来评估。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的腺病毒疾病免疫治疗试验奠定了基础。预计各国这项工作将改善接受干细胞移植的病人的存活率。