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: 7564061
• 负责人: Asha Bhaskaran Pillai
• 金额: $ 4.22万
• 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 2009-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564061
• 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; Dose; Engraftment; Exhibits; Gastrointestinal tract structure; Generations; 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; Organ; Organ Transplantation; Oryctolagus cuniculus; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Principal Investigator; Procedures; Production; Protocols documentation; 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; allotransplant; base; beta Thalassemia; conditioning; cytokine; 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; treatment strategy

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）：