REGULATORY T CELLS, MIXED CHIMERISM: A NOVEL TRANSPLANT STRATEGY FOR THALASSEMIAS

调节性 T 细胞，混合嵌合：地中海贫血的新型移植策略

• 批准号: 7385568
• 负责人: Asha Bhaskaran Pillai
• 金额: $ 13.06万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-06 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385568
• 关键词: Acute; Acute Graft Versus Host Disease; Adoptive Transfer; Alloantigen; Allogeneic Bone Marrow Transplantation; Allogenic; Allografting; Antithymoglobulin; Bone Marrow; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Transplantation; Cell secretion; Cells; Chimerism; Clinical; Clinical Trials; Colon; Complication; Condition; Dose; Engraftment; Exhibits; Gastrointestinal tract structure; Generations; Genus Cola; Hematological Disease; Hematopoietic; Histocompatibility; Homologous Transplantation; Human; Immune; Immune response; Immunity; In Vitro; Inbred BALB C Mice; Incidence; Infection; Inflammatory; Injury; Interleukin-10; Interleukin-4; Interleukins; Kidney Transplantation; Knockout Mice; Laboratories; Liver; Lymphatic Irradiation; Maintenance; Malignant Neoplasms; Marrow; Mediating; Methods; Modeling; Mus; Non-Malignant; Numbers; Organ; Organ Transplantation; Oryctolagus cuniculus; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Principal Investigator; Procedures; Production; Protocols documentation; Range; Regulation; Relative (related person); Role; Serum; Side; Skin; Solid; Sorting - Cell Movement; Spleen; Splenocyte; Stem cells; Syndrome; System; T-Cell Depletion; T-Lymphocyte; TNFRSF11B gene; Thalassemia; Thalassemia intermedia; Toxic effect; Transplant Recipients; Transplantation; Transplantation Conditioning; Treatment Protocols; Whole-Body Irradiation; Work; abstracting; base; beta Thalassemia; conditioning; cytokine; day; graft failure; graft vs host disease; human disease; immune function; in vivo; insight; intraperitoneal; killer T cell; mouse model; novel; preclinical study; prevent; progenitor; programs; response; stem; thymocyte

DESCRIPTION (provided by applicant): The long-range objectives of the proposed study are to determine the role of regulatory T cells in protection against graft-versus-host disease (GVHD) in total lymphoid irradiation/anti-thymocyte serum host conditioning (TLI/ATS), the murine model of a successful human protocol for non-myeloablative bone marrow transplantation (BMT), and to apply this strategy for treatment of thalassemia. This work proposes to further elucidate factors involved in the generation of donor regulatory CD4+CD25+ T cells (CD4+CD25high Tregs) after TLI/ATS, and to determine whether TLI/ATS can be considered to treat thalassemias. This proposal stems from the finding that TLI/ATS-treated hosts given major histocompatibility (MHC)- mismatched BMT are protected from lethal GVHD, whereas TLI/ATS treated NK T cell-deficient and IL-4- deficient hosts develop lethal GVHD, and that BMT from CD4-deficient, IL-4 deficient, and IL-10-deficient donors to wild-type TLI/ATS treated hosts also results in lethal GVHD. In investigating this, we determined that donor CD4+CD25high Tregs are significantly increased after BMT in wild-type TLI/ATS-treated hosts, lost after BMT in NK T cell-deficient hosts, and partially regained upon adoptive transfer of NK T cells to NK T cell-deficient hosts. The hypotheses of this proposal are that: 1) Host regulatory NK T cells mediate GVHD protection via their secretion of IL-4, 2) Host NK T cells allow the maintenance and/or expansion of donor CD4+CD25high Tregs, and 3) TLI/ATS host treatment and allogeneic BMT can allow correction of the thalassemic phenotype without GVHD, in a mouse model of human (3-thalassemia. Using adoptive transfers of purified NK T cells and MHC-mismatched mouse transplants in wild-type and knockout mice, our specific aims are to: 1) Determine the role of host NK T cell IL-4 secretion in inhibition of donor T cell expansion following BMT, 2) Determine the specific donor CD4+ T cell population(s) responsible for GVHD protection, and whether these are regulatory CD4+ T cells, 3) Determine the role of host NK T cells in the generation of donor regulatory CD4+ T cells, and 4) Determine whether BMT after TLI/ATS in thalassemic mice can allow stable donor engraftment without GVHD, and thereby correct the thalassemic phenotype. The proposed work will provide substantial insights into the regulation of donor T cell responses after bone marrow transplantation, and will help define key interactions between innate (NK T) cells and adaptive (CD4*CD25h'9h) immune regulatory cells. This could provide new strategies for the modulation of immune function in treatment of infections, auto-immunity, or cancer, and in transplantation for blood diseases. (End of Abstract)

描述（由申请人提供）： 拟议的研究的远距离目标是确定调节性T细胞在防止移植物抗宿主疾病（GVHD）中的作用，在总淋巴样辐照/抗心理细胞血清宿主条件（TLI/ATS）中，这是一种成功的人类协议的鼠模型，该模型是针对非微骨骨骨摩尔骨架的策略进行过多的（bmrow shorts）的（bmyelo bone骨骼）的策略（bmrow）。这项工作建议进一步阐明与供体调节性CD4+CD25+T细胞（CD4+CD25高tregs）产生TLI/ATS之后的因素，并确定是否可以考虑使用TLI/ATS来治疗tli/ATS。该提议源于以下发现：TLI/ATS处理的宿主给定的主要组织反应性（MHC） - 不匹配的BMT受到致命性GVHD的保护，而TLI/ATS治疗的NK T细胞缺陷型和IL-4-缺陷宿主则会产生Lethal GVHD的限制性和cd4-defient cd4-defient cd4-defient， IL-10缺乏对野生型TLI/ATS处理的宿主的供体也导致致命的GVHD。在调查此过程中，我们确定BMT在野生型TLI/ATS处理的宿主中BMT后的供体CD4+CD25高的Treg显着增加，在NK T细胞缺陷型宿主中BMT损失后损失，并且在NK T细胞对NK T细胞对NK T细胞缺乏的宿主的过继转移后部分重新恢复。该提案的假设是：1）宿主调节性NK T细胞通过其分泌IL-4，2）宿主NK T细胞允许维持和/或扩展供体CD4+CD25-HIGH TREG，以及3）TLI/AT/AT/ATS宿主治疗和同种型BMT的均可允许人类的鼠类thal sassass sasssass nons govhemematize thal sasssass the thal sassspecty sype- （3-甲性贫血。使用纯化的NK T细胞和MHC匹配的小鼠移植物在野生型和基因敲除小鼠中的传递转移，我们的具体目的是：1）确定宿主NK T细胞IL-4分泌在抑制供体T细胞扩展中的作用，并确定这些特定的供体donor CD4+ T CD4+ T CD4+ T CD4+ T CD4+ T）的作用（S） CD4+ T细胞，3）确定宿主NK T细胞在供体调节性CD4+ T细胞中的产生中的作用，4）确定TLI/ATS在TLI/ATS中的BMT是否可以在没有GVHD的情况下允许稳定的供体植入，从而纠正了Thalassemic表型。拟议的工作将为骨髓移植后调节供体T细胞反应的调节提供大量见解，并有助于定义先天细胞（NK T）细胞和适应性（CD4*CD25H'9H）免疫调节细胞之间的关键相互作用。这可以为调节免疫功能在治疗感染，自身免疫性或癌症以及血液疾病移植方面提供新的策略。 （抽象的结尾）