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:
- 金额:$ 13.06万
- 依托单位:
- 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:
- 关键词:AcuteAcute Graft Versus Host DiseaseAdoptive TransferAlloantigenAllogeneic Bone Marrow TransplantationAllogenicAllograftingAntithymoglobulinBone MarrowBone Marrow TransplantationCD4 Positive T LymphocytesCD8B1 geneCell TransplantationCell secretionCellsChimerismClinicalClinical TrialsColonComplicationDoseEngraftmentExhibitsGastrointestinal tract structureGenerationsHematological DiseaseHematopoieticHistocompatibilityHomologous TransplantationHumanIL2RA geneImmuneImmune responseImmunityIn VitroInbred BALB C MiceIncidenceInfectionInflammatoryInjuryInterleukin-10Interleukin-4InterleukinsKidney TransplantationKnockout MiceLaboratoriesLiverLymphatic IrradiationMaintenanceMalignant NeoplasmsMarrowMediatingMethodsModelingMusNon-MalignantOrganOrgan TransplantationOryctolagus cuniculusPatientsPeripheralPeripheral Blood Mononuclear CellPhenotypePlayPopulationPrincipal InvestigatorProceduresProductionProtocols documentationRegimenRegulationRegulatory T-LymphocyteRelative (related person)RoleSerumSideSkinSolidSorting - Cell MovementSpleenSplenocyteStem cellsSyndromeSystemT cell responseT-Cell DepletionT-LymphocyteTNFRSF11B geneThalassemiaThalassemia intermediaToxic effectTransplant RecipientsTransplantationTransplantation ConditioningWhole-Body IrradiationWorkallotransplantbasebeta Thalassemiaconditioningcytokinegraft failuregraft vs host diseasehematopoietic cell transplantationhuman diseaseimmune functionin vivoinsightintraperitonealkiller T cellmouse modelnovelpreclinical studypreventprogenitorprogramsresponsestemthymocytetreatment 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)
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:
- 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:
- 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:
- 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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