Rebuilding Immunity for Survival

重建免疫力以求生存

• 批准号: 7192440
• 负责人: Lee Marshall Nadler
• 金额: $ 367.86万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7192440
• 关键词: Acute; Allogenic; Cells; Chronic; Clinical; Clinical Investigator; Clinical Trials; Collaborations; Common Lymphoid Progenitor; Coupled; Development; Fostering; Goals; Hematopoietic Stem Cell Transplantation; Human; Immune; Immune system; Immunity; Immunologist; Individual; International; Modeling; Mus; Natural Killer Cells; Pathway interactions; Patients; Relapse; Stem cells; T-Cell Development; T-Lymphocyte; Technology; Testing; Therapeutic Index; Toxic effect; Translating; Translations; Transplantation; Treatment Protocols; abstracting; catalyst; concept; conditioning; graft vs host disease; human disease; improved; pathogen; prevent; programs; reconstitution; repaired; sound; tumor

Revised Abstract: DESCRIPTION (provided by applicant): If the immune deficiency associated with allogeneic hematopoietic stem cell transplantation (HSCT) could be corrected or even prevented, the therapeutic index of allogeneic HSCT would be significantly improved and its impact greatly enhanced. Our hypothesis is that understanding the pathways that regulate early T cell development, maturation, differentiation, and acquisition of function coupled with the development and clinical translation of specific approaches to enhance each of these steps while controlling alloreactivity will be necessary to achieve this objective. Over the past 2 years, an international team of experts composed of stem cell biologists, basic and clinical immunologists, transplant biologists, transplant clinical investigators, and biostatisticians has been assembled to attack this problem. Each of these individuals brings a strong translational track record and commitment to this challenge. Our goal is to develop translational strategies to foster rapid and, if possible, complete immune reconstitution after HSCT in order to eliminate the multiple complications that accompany acute and chronic immune deficiency. We propose to develop, enable, and standardize these technologies which will in turn impact favorably on GVHD, regimen-related toxicity, and relapse. To this end, seven Projects and five Cores have been developed. Projects 1 and 2 will study the common lymphoid progenitor cell in mice and humans in order to develop strategies to enhance HSCT immune reconstitution. Projects 3 and 4 will attempt to prevent and/or repair HSCT associated thymic damage in murine models and translate these strategies to patients undergoing allogeneic HSCT. Project 5 will attempt to reduce the intensity of conditioning regimens by using veto and regulatory cells to control host anti-donor alloreactivity. This approach has the potential to improve immune reconstitution. Project 6 will attempt to improve ex vivo strategies to anergize donor anti-host alloreactive T cells to control GVHD thereby allowing a broad functional T cell repertoire to be adoptively transferred to HSCT patients. Project 7 will adoptively transfer of alloreactive NK cells following HSCT in order to reduce the intensity of conditioning and tumor relapse. Project 7 also proposes to adoptively transfer T cells of both narrow and broad repertoire to control pathogens. These Projects rely upon the Clinical Trials, Immune Assessment, Biostatistical, Tetramer, and Administrative Cores to provide a platform to foster and facilitate planning, translation, and collaboration. We see this Program as a catalyst to bring others in the field together. The next decade will test the concept whether specific manipulation of the immune system to treat human disease is sound and we are confident that this Program will significantly contribute to this effort.

修订摘要：描述（由申请人提供）：如果可以纠正甚至预防与同种异体造血干细胞移植（HSCT）相关的免疫缺陷，则同种异体HSCT的治疗指数将得到显着改善，并且其影响大大增强。我们的假设是，了解调节早期T细胞发育，成熟，分化和功能的获取的途径以及特定方法的开发和临床翻译以增强这些步骤，同时控制同种反应性，以实现这一目标。 在过去的两年中，由干细胞生物学家，基本和临床免疫学家，移植生物学家，移植临床研究者和生物统计学家组成的国际专家团队已组成，以攻击这一问题。这些人中的每一个都带来了强大的翻译记录和对这一挑战的承诺。我们的目标是制定转化策略，以促进快速的快速，并在HSCT之后进行完全的免疫重建，以消除急性和慢性免疫缺陷伴随的多种并发症。我们建议开发，启用和标准化这些技术，而这些技术反过来将对GVHD，与方案相关的毒性和复发产生有益的影响。为此，已经开发了七个项目和五个核心。 项目1和2将研究小鼠和人类中常见的淋巴祖细胞，以制定增强HSCT免疫重建的策略。项目3和4将试图预防和/或修复HSCT在鼠模型中相关的胸腺损伤，并将这些策略转化为接受同种异体HSCT的患者。项目5将尝试通过使用否决和调节细胞来控制宿主抗抑制同质反应性，以降低调理方案的强度。这种方法有可能改善免疫结构。项目6将尝试改善离体策略，以吞噬供体抗宿主同种异体T细胞，以控制GVHD，从而使宽阔的功能性T细胞库可通过传递给HSCT患者。项目7将在HSCT之后采用同种反应性NK细胞转移，以降低调节和肿瘤复发的强度。项目7还建议将狭窄和广泛曲目的T细胞转移到控制病原体中。这些项目依靠临床试验，免疫评估，生物统计，四聚体和行政核心来提供一个平台来促进和促进计划，翻译和协作。 我们认为该程序是将其他人聚集在一起的催化剂。接下来的十年将测试该概念是否对治疗人类疾病的免疫系统进行具体操纵，我们相信该计划将对这一努力产生重大贡献。