Elucidating the role of T-regs in engraftment, GVHD, and DLI immunotherapy

阐明 T 调节细胞在植入、GVHD 和 DLI 免疫治疗中的作用

• 批准号: 8018645
• 负责人: CHRISTENE A HUANG
• 金额: $ 42.17万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018645
• 关键词: Ablation; Advanced Development; Animals; Aplastic Anemia; Biological Assay; Blood Cells; CD3 Antigens; Cell Separation; Cell Transplantation; Cell-Mediated Cytolysis; Cells; Child; Clinic; Clinical; Coculture Techniques; Cyclosporine; Data; Development; Disease; Dose; Engraftment; Ensure; Excision; Failure; Family suidae; Genetic; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Hemoglobinopathies; Hereditary Disease; Human; Immune; Immune response; Immune system; Immunologic Deficiency Syndromes; Immunotherapy; Immunotoxins; In Vitro; Infection; Infusion procedures; Inherited; Laboratories; Leukapheresis; Leukocytes; Life; Lymphocyte; Lysosomal Storage Diseases; Miniature Swine; Modeling; Outcome; Parents; Peripheral Blood Mononuclear Cell; Population; Pre-Clinical Model; Procedures; Protocols documentation; Regulatory T-Lymphocyte; Research; Research Personnel; Rodent; Role; Stem cells; T-Cell Depletion; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Toxic effect; Translating; Translations; Transplantation Tolerance; Whole-Body Irradiation; base; conditioning; gene therapy; graft function; graft vs host disease; immunoregulation; in vivo; innovation; leukemia/lymphoma; novel; peripheral blood; pre-clinical; response

DESCRIPTION (provided by applicant): Hematopoietic cell transplantation (HCT) can cure genetic blood disorders through the replacement of defective blood cells by healthy cells. However, life-threatening complications limit the use of HCT therapy in the clinic. Complications in the recipient result from toxic conditioning and from graft-versus-host disease (GVHD), a condition where the donor T-cells attack the recipient (host) tissues. Complete, prolonged depletion of both donor and host T cells permits stable engraftment of donor cells using reduced-intensity conditioning in rodents, without GVHD. However, complete T cell depletion is difficult to achieve in humans and infections, hematopoietic failure, and GVHD remain major complications of clinical HCT. Similar to outcomes in humans, miniature swine develop severe GVHD, infectious complications, or hematopioetic failure following standard clinical myeloablative conditioning and HCT. The investigators recently developed a novel, mild, preclinical protocol for HCT which permits donor cells to engraft without GVHD. Indeed, the treatment of miniature swine with a low-dose of total body irradiation, partial T-cell depletion, and a short course of cyclosporine A has reliably established donor HC engraftment without GVHD despite infusion of a very high dose of T-cell replete haploidentical (e.g., parent-into-child) HCT. Surprisingly, additional treatment with donor leukocyte infusion (DLI), a procedure known to ensure full replacement of HC in engrafted rodents, did not result in full (donor) hematopoietic replacement. The investigators surmise that the persistence of donor and recipient T cells in treated pigs promotes HC engraftment, inhibits GVHD, but also hinders the DLI conversion effect. Indeed, preliminary data suggest that regulatory cells persist in treated animals and inhibit both GVHD and DLI alloreactivity. Thus, the goal of this project is to elucidate the immunological mechanisms responsible for facilitating engraftment without GVHD, and to test new strategies to restore the DLI conversion effect in swine. The investigators hypothesize that immune modulation with regulatory cell involvement promotes engraftment and inhibits GVHD and DLI effects by inactivating donor, recipient, and DLI alloreactive T-cells. This hypothesis will be tested by the following specific aims, to: 1) elucidate the immunological mechanisms controlling GVH and HVG alloreactive T cells in vivo following HCT; and 2) restore the ability of DLI to enhance donor engraftment levels without GVHD through specific immune modulation. This project is innovative in that it investigates approaches for HCT that harness the immunomodulatory capacities of the immune system, rather than immune ablation, to promote better engraftment with fewer complications. The long-term goal of these studies is to translate promising protocols for parent-into-child HCT and DLI to the clinic. Successful translation would provide a cure for many screenable genetic disorders including hemoglobinopathies, lysosomal storage diseases, inherited aplastic anemias, and primary immunodeficiency diseases. If the aims of this application are achieved, these results could have a major impact on clinical HCT approaches. RELEVANCE: Toxicities and complications associated with hematopoietic cell transplantation (HCT) currently limit this curative therapy for genetic blood disorders in the clinic. The goal of this application is to understand the immunological mechanisms responsible for facilitating high-level haploidentical (e.g., parent into child) donor hematopoietic cell engraftment without complications. The long-term goal of these studies is to translate promising nontoxic HCT protocols using parental donors to replace diseased blood cells and cure genetic blood disorders in children.

描述（由申请人提供）：造血细胞移植（HCT）可以通过用健康细胞替代缺陷血细胞来治疗遗传性血液疾病。 然而，危及生命的并发症限制了HCT疗法在临床中的使用。 受体的并发症是由毒性条件和移植物抗宿主病（GVHD）引起的，GVHD是供体T细胞攻击受体（宿主）组织的一种情况。 供体和宿主T细胞的完全、长时间消耗允许在啮齿动物中使用降低强度的调节稳定植入供体细胞，而不发生GVHD。 然而，在人类中难以实现完全T细胞耗竭，并且感染、造血衰竭和GVHD仍然是临床HCT的主要并发症。 与人类结局相似，小型猪在标准临床清髓性预处理和HCT后发生严重GVHD、感染并发症或造血衰竭。 研究人员最近开发了一种新的，温和的，临床前的HCT方案，允许供体细胞移植而不发生GVHD。 事实上，用低剂量的全身照射、部分T细胞耗竭和短疗程的环孢菌素A治疗小型猪已经可靠地建立了供体HC植入而没有GVHD，尽管输注了非常高剂量的T细胞完全单倍体相合（例如，父母到孩子）HCT。 令人惊讶的是，供体白细胞输注（DLI）的额外治疗（一种已知可确保移植啮齿动物中HC完全替代的程序）并未导致完全（供体）造血替代。 研究者推测，供体和受体T细胞在治疗猪中的持续存在促进了HC植入，抑制了GVHD，但也阻碍了DLI转化效应。 事实上，初步数据表明，调节细胞持续在治疗的动物和抑制GVHD和DLI同种异体反应。 因此，本项目的目标是阐明负责促进植入而不发生GVHD的免疫学机制，并测试恢复猪DLI转换效应的新策略。 研究者推测，调节细胞参与的免疫调节通过使供体、受体和DLI同种异体反应性T细胞失活来促进移植并抑制GVHD和DLI效应。 该假设将通过以下特定目的进行测试，以：1）阐明HCT后体内控制GVH和HVG同种异体反应性T细胞的免疫学机制;和2）通过特异性免疫调节恢复DLI增强供体植入水平而无GVHD的能力。 该项目的创新之处在于，它研究了HCT的方法，这些方法利用免疫系统的免疫调节能力，而不是免疫消融，以促进更好的植入，减少并发症。 这些研究的长期目标是将有前景的父母到孩子HCT和DLI的协议转化为临床。 成功的翻译将为许多可筛选的遗传性疾病提供治愈方法，包括血红蛋白病、溶酶体贮积病、遗传性再生障碍性贫血和原发性免疫缺陷病。 如果本申请的目的得以实现，这些结果可能会对临床HCT方法产生重大影响。 相关性：目前，造血细胞移植（HCT）的毒性和并发症限制了临床上对遗传性血液病的治疗。 本申请的目标是了解负责促进高水平单倍体相合的免疫学机制（例如，父母到孩子）供者造血细胞移植而没有并发症。 这些研究的长期目标是转化有希望的无毒HCT方案，使用父母供体来替代患病的血细胞并治愈儿童的遗传性血液疾病。