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

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.
拟议研究的长期目标是确定调节性T细胞在保护中的作用 全淋巴照射/抗胸腺细胞血清宿主抗移植物抗宿主病(GVHD) 条件化(TLI/ATS)--成功的人类非清髓性骨移植方案的小鼠模型 骨髓移植(BMT),并应用这一策略治疗地中海贫血。这项工作提出了 为了进一步阐明与供体调节性CD4+CD25+T细胞(CD4+CD25High)产生有关的因素 TLI/ATS后),并确定TLI/ATS是否可被考虑用于治疗地中海贫血。这 这一建议源于TLI/ATS处理的宿主具有主要组织相容(MHC)- 不相合的骨髓移植可以预防致死性GVHD,而TLI/ATS治疗的NK T细胞缺陷和IL-4- 缺陷宿主会发展成致命性移植物抗宿主病,而来自CD4缺陷、IL-4缺陷和IL-10缺陷骨髓移植 对野生型TLI/ATS治疗宿主的捐赠者也会导致致命性GVHD。在调查这件事时,我们确定 野生型TLI/ATS处理的宿主骨髓移植后供者CD4+CD25High Tregs显著增加,丢失 在NK T细胞缺陷的宿主中进行骨髓移植,并通过过继转移NK T细胞到NK T部分恢复 缺乏细胞的宿主。这一建议的假设是:1)宿主调节性NK T细胞介导GVHD 通过分泌IL-4进行保护,2)宿主NK T细胞允许维持和/或扩大供者 3)TLI/ATS宿主治疗和异基因骨髓移植可以纠正 在人类(3-地中海贫血)小鼠模型中,无GVHD的地中海贫血表型。使用收养转移 在野生型和基因敲除小鼠中进行纯化的NK T细胞和MHC不匹配的小鼠移植,我们的特异性 目的:1)确定宿主NK T细胞IL-4分泌在抑制供者T细胞增殖中的作用 骨髓移植后,2)确定负责GVHD保护的特异性供者CD_4~+T细胞群(S), 以及这些细胞是否是调节性的CD4+T细胞,3)决定宿主NK T细胞在产生 供体调节性CD4+T细胞,以及4)确定地中海贫血小鼠TLI/ATS后的BMT是否可以 稳定的供者植入,无需移植物抗宿主病,从而纠正地中海贫血表型。建议数 这项工作将为骨髓后供者T细胞反应的调节提供实质性的见解 移植,并将有助于确定先天(NK T)细胞和适应性之间的关键相互作用 (CD4*CD25h‘9h)免疫调节细胞。这可能为免疫调节提供新的策略。 用于治疗感染、自身免疫或癌症,以及用于血液疾病的移植。

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)
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.
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:
  • 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
Diagnostic Clues to Human Herpesvirus 6 Encephalitis and Wernicke Encephalopathy After Pediatric Hematopoietic Cell Transplantation.
  • DOI:
    10.1177/0883073814560628
  • 发表时间:
    2015-09
  • 期刊:
  • 影响因子:
    1.9
  • 作者:
    Sadighi Z;Sabin ND;Hayden R;Stewart E;Pillai A
  • 通讯作者:
    Pillai A
Regulatory immunotherapy in bone marrow transplantation.
骨髓移植中的调节性免疫治疗。
  • DOI:
    10.1100/2011/768948
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Morales-Tirado,Vanessa;Luszczek,Wioleta;vanderMerwe,Marie;Pillai,Asha
  • 通讯作者:
    Pillai,Asha
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Asha Bhaskaran Pillai其他文献

Asha Bhaskaran Pillai的其他文献

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{{ truncateString('Asha Bhaskaran Pillai', 18)}}的其他基金

NOVEL INNATE MECHANISMS OF IMMUNE TOLERANCE INDUCTION IN ALLOGENEIC HCT FOR HEMOGLOBINOPATHIES
血红蛋白病同种异体 HCT 中免疫耐受诱导的新先天机制
  • 批准号:
    10067378
  • 财政年份:
    2018
  • 资助金额:
    $ 13.06万
  • 项目类别:
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:
    7881001
  • 财政年份:
    2008
  • 资助金额:
    $ 13.06万
  • 项目类别:
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
  • 财政年份:
    2008
  • 资助金额:
    $ 13.06万
  • 项目类别:
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
  • 财政年份:
    2008
  • 资助金额:
    $ 13.06万
  • 项目类别:
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:
    7991794
  • 财政年份:
    2008
  • 资助金额:
    $ 13.06万
  • 项目类别:
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
  • 财政年份:
    2008
  • 资助金额:
    $ 13.06万
  • 项目类别:

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