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

基本信息

批准号：
8197519
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
项目类别：
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/8197519
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 IL2RA gene 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 allotransplant base beta Thalassemia conditioning cytokine graft failure graft vs host disease hematopoietic cell transplantation human disease immune function in vivo insight intraperitoneal killer T cell mouse model novel preclinical study prevent progenitor programs response stem thymocyte treatment strategy

项目摘要

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.

拟议研究的远程目标是确定调节性T细胞在保护中的作用总淋巴辐照/抗抑制细胞血清宿主中的抗移植物抗宿主病（GVHD）调理（TLI/ATS），这是成功人类规程的非毛毛骨的鼠模型骨髓移植（BMT），并将这种策略应用于丘脑贫血。这项工作提出了进一步阐明供体调节CD4+CD25+T细胞产生的因素（CD4+CD25高 tregs）在TLI/ATS之后，并确定是否可以考虑使用TLI/ATS来治疗thalassecnias。这提案源于以下发现：TLI/ATS处理的宿主给定主要的组织相容性（MHC） - 不匹配的BMT受到致命GVHD的保护，而TLI/ATS处理的NK T细胞缺陷型和IL-4-- 缺乏宿主会产生致命的GVHD，并且来自CD4缺陷，IL-4缺陷和IL-10缺陷的BMT 对野生型TLI/ATS处理的宿主的捐助者也导致致命的GVHD。在调查这一点时，我们确定了 BMT在野生型TLI/ATS处理的宿主中，供体CD4+CD25高的Treg显着增加，损失在NK T细胞缺陷型宿主中BMT之后，并部分恢复了NK T细胞的过继转移细胞缺陷宿主。该提议的假设是：1）宿主调节NK T细胞介导GVHD 通过分泌IL-4的保护，2）宿主NK T细胞允许维护和/或扩展供体 CD4+CD25高treg和3）TLI/ATS宿主治疗和同种异体BMT可以纠正在人类的小鼠模型中，没有GVHD的Thalassemic表型（3-甲性贫血。纯化的NK T细胞和MHC不匹配的小鼠在野生型和敲除小鼠中的移植，我们的特定目的是：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 BMT之后，2）确定负责GVHD保护的特定供体CD4+ T细胞种群，这些是否是调节性CD4+ T细胞，3）确定宿主NK T细胞在生成中的作用供体调节性CD4+ T细胞，4）确定TLI/ATS在TLI/ATS中的BMT是否可以允许没有GVHD的稳定供体植入，从而纠正了丘脑病表型。提议工作将为骨髓后的供体T细胞反应的调节提供大量见解移植，并将有助于定义先天（NK T）细胞和自适应之间的关键相互作用（CD4*CD25H'9H）免疫调节细胞。这可以为调节免疫提供新的策略在治疗感染，自身免疫性或癌症以及血液疾病移植方面的功能。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recipient myeloid-derived immunomodulatory cells induce PD-1 ligand-dependent donor CD4+Foxp3+ regulatory T cell proliferation and donor-recipient immune tolerance after murine nonmyeloablative bone marrow transplantation.

DOI：
10.4049/jimmunol.1302191
发表时间：
2013-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
van der Merwe M;Abdelsamed HA;Seth A;Ong T;Vogel P;Pillai AB
通讯作者：
Pillai AB

Phase I study of the safety and pharmacokinetics of plerixafor in children undergoing a second allogeneic hematopoietic stem cell transplantation for relapsed or refractory leukemia.

DOI：
10.1016/j.bbmt.2014.04.020
发表时间：
2014-08
期刊：
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
影响因子：
0
作者：
Srinivasan A;Panetta JC;Cross SJ;Pillai A;Triplett BM;Shook DR;Dallas MH;Hartford C;Sunkara A;Kang G;Jacobsen J;Choi J;Leung W
通讯作者：
Leung W

Favorable preliminary results using TLI/ATG-based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia.

DOI：
10.1111/j.1399-3046.2011.01542.x
发表时间：
2011-09
期刊：
Pediatric transplantation
影响因子：
1.3
作者：
Pillai A;Hartford C;Wang C;Pei D;Yang J;Srinivasan A;Triplett B;Dallas M;Leung W
通讯作者：
Leung W

Successful allogeneic hematopoietic cell engraftment after a minimal conditioning regimen in children with relapsed or refractory solid tumors.

在患有复发或难治性实体瘤的儿童中，经过最低限度的调理方案后成功进行同种异体造血细胞移植。

DOI：
10.1016/j.bbmt.2012.10.001
发表时间：
2013
期刊：
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
影响因子：
0
作者：
Shook,DavidR;Triplett,BrandonM;Srinivasan,Ashok;Hartford,Christine;Dallas,MariH;Pillai,Asha;Laver,Joseph;Leung,Wing
通讯作者：
Leung,Wing

Regulatory immunotherapy in bone marrow transplantation.

骨髓移植中的调节性免疫治疗。