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: 7741678
• 负责人: Asha Bhaskaran Pillai
• 金额: $ 13.06万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 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/7741678
• 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; Regimen; Regulation; Regulatory T-Lymphocyte; Relative (related person); Role; Serum; Side; Skin; Solid; Sorting - Cell Movement; Spleen; Splenocyte; Stem cells; Syndrome; System; T cell response; T-Cell Depletion; T-Lymphocyte; TNFRSF11B gene; Thalassemia; Thalassemia intermedia; Toxic effect; Transplant Recipients; Transplantation; Transplantation Conditioning; 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）： 该研究的长期目标是确定调节性T细胞在全淋巴照射/抗胸腺细胞血清宿主调节（TLI/ATS）中保护移植物抗宿主病（GVHD）的作用，这是一种成功的非清髓性骨髓移植（BMT）的人类方案的小鼠模型，并将此策略应用于地中海贫血的治疗。本研究拟进一步阐明TLI/ATS后供体调节性CD 4 + CD 25 + T细胞（CD 4 + CD 25 high Tcls）生成的相关因素，并确定TLI/ATS是否可用于治疗地中海贫血。这一提议源于以下发现：给予主要组织相容性（MHC）错配的BMT的TLI/ATS处理的宿主被保护免于致死性GVHD，而TLI/ATS处理的NK T细胞缺陷和IL-4缺陷的宿主发展致死性GVHD，并且来自CD 4缺陷、IL-4缺陷和IL-10缺陷的供体的BMT至野生型TLI/ATS处理的宿主也导致致死性GVHD。在研究中，我们确定了供体CD 4 + CD 25 high T细胞在野生型TLI/ATS处理的宿主中BMT后显著增加，在NK T细胞缺陷的宿主中BMT后丢失，并且在将NK T细胞过继转移到NK T细胞缺陷的宿主后部分恢复。该建议的假设是：1）宿主调节性NK T细胞通过分泌IL-4介导GVHD保护，2）宿主NK T细胞允许供体CD 4 + CD 25高T细胞的维持和/或扩增，和3）在人β-地中海贫血的小鼠模型中，TLI/ATS宿主治疗和同种异体BMT可以允许在没有GVHD的情况下纠正地中海贫血表型。在野生型和基因敲除小鼠中使用纯化NK T细胞的过继转移和MHC不匹配的小鼠移植，我们的具体目标是：1）确定宿主NK T细胞IL-4分泌在抑制BMT后供体T细胞扩增中的作用，2）确定负责GVHD保护的特异性供体CD 4 + T细胞群，以及这些细胞是否是调节性CD 4 + T细胞，3）确定宿主NK T细胞在供体调节性CD 4 + T细胞产生中的作用，和4）确定地中海贫血小鼠中TLI/ATS后的BMT是否可以允许稳定的供体植入而没有GVHD，从而纠正地中海贫血表型。拟议的工作将为骨髓移植后供体T细胞反应的调节提供实质性见解，并将帮助定义先天性（NK T）细胞和适应性（CD 4 * CD 25 h '9 h）免疫调节细胞之间的关键相互作用。这可能为在治疗感染、自身免疫或癌症以及血液病移植中调节免疫功能提供新的策略。(End摘要）