Nonmyeloablative Allografts in DLA-haploidentical Dogs: Engraftment and GVHD
DLA 单倍体狗的非清髓性同种异体移植:移植和 GVHD
基本信息
- 批准号:7478449
- 负责人:
- 金额:$ 41.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-08-01 至 2011-07-31
- 项目状态:已结题
- 来源:
- 关键词:AllogenicAllograftingAntibodiesAntigensAutologousBiologicalBismuthBlood CellsBreedingCD45 AntigensCanis familiarisCell Adhesion MoleculesCell TransplantationCellsChimeric ProteinsChimerismClinicalClinical TrialsConditionCyclosporine/Mycophenolate MofetilCytotoxic T-Lymphocyte-Associated Protein 4DevelopmentDoseDrug resistanceEngraftmentGenesGoalsGrantGranulocyte Colony-Stimulating FactorHLA AntigensHematopoieticHigh Dose ChemotherapyHost vs Graft ReactionHumanImmunoglobulinsImmunologicsImmunosuppressive AgentsLabelLeukocytesLymphocyteMarrowMediatingMethotrexateMonoclonal AntibodiesNatural Killer CellsPatientsPre-Clinical ModelPreventionPrincipal InvestigatorRadioisotopesRangeRateRecoveryResidual stateSirolimusStem cellsT-LymphocyteTNFSF5 geneTinToxic effectTranslatingTranslationsTransplantationTreatment ProtocolsWorkcellular transductionchemotherapygraft vs host diseasegraft vs host reactionkiller T cellmycophenolate mofetilprogramsresponsetemozolomide
项目摘要
The long-term objective of this project is to develop a safe and reliable nonmyeloablative approach at
hematopoietic cell transplantation (HCT) from dog leukocyte antigen (DLA)-haploidentical donors, which can
be translated into clinical trials. The studies will focus on the bi-directional immunologic barriers, host-versus-graft
(HVG) and graft-versus-host (GVH) reactions, which must be overcome in order to achieve both
uniform and sustained hematopoietic engraftment and graft-host tolerance. Two goals were pursued during
the current grant period. One included extension of work in DLA-identical littermates in which we
successfully substituted monoclonal antibodies (MAbs) directed at either TCRalpha-beta or the ubiquitous
hematopoietic antigen, CD45, which were labeled with an alpha-emitting radionuclide Bismuth-213 (213Bi), for
2 Gy TBI. We also established successful DLA-haploidentical grafts when recipients were treated first with
an anti-CD44 antibody combined with 4.5 Gy TBI and then given mycophenolate mofetil (MMF) and
cyclosporine (CSP) after HCT for control of residual HVG reactions and for GVHD prevention. However,
when the TBI dose was decreased to the sublethal range of 2 Gy, the engraftment rate declined to 50%,
while the remainder of the dogs eventually rejected their grafts and survived with autologous marrow
recovery. Also, GVHD control, which is largely T-cell mediated, has not been uniform.
The current proposal seeks to continue the studies on DLA-haploidentical grafts since development of
safe approaches will expand the choice of potential donors. Two principal experimental approaches will be
taken. One involves combining low-dose TBI with relatively non-toxic biological and pharmacological
immunosuppressive agents, including 213Bi-labeled antibodies to natural killer (NK) cells, all aimed at
reducing both host NK and T cell responses and T cell responsiveness of the graft. The other is to administer
chemotherapy early after transplant to not only control GVHD but also facilitate engraftment. After we have
determined the optimal tinning and dosing of posttransplantation chemotherapy, we will evaluate the use of
donor cells transduced with drug resistance genes which will allow using higher doses of posttransplantation
chemotherapy for both induction of donor chimerism and control of GVHD. GVHD prevention will also
include control of donor lymphocyte replication with certain immunosuppressive agents, e.g., MMF and
sirolimus, combined with blockers of T-cell costimulation.
Our ultimate aim is to develop allogeneic HCT strategies for patients with alternative donors with the
least short- and long-term toxicities, which can be successfully applied to human patients.
该项目的长期目标是开发一种安全可靠的非清髓方法
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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BRENDA MARIE SANDMAIER其他文献
BRENDA MARIE SANDMAIER的其他文献
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{{ truncateString('BRENDA MARIE SANDMAIER', 18)}}的其他基金
Alpha Emitter Labeled Anti-T Cell Antibody: Targeting Latent HIV Infected Cells
Alpha 发射体标记的抗 T 细胞抗体:针对潜伏的 HIV 感染细胞
- 批准号:
9301083 - 财政年份:2016
- 资助金额:
$ 41.46万 - 项目类别:
Alpha Emitter Labeled Anti-T Cell Antibody: Targeting Latent HIV Infected Cells
Alpha 发射体标记的抗 T 细胞抗体:针对潜伏的 HIV 感染细胞
- 批准号:
9327864 - 财政年份:2016
- 资助金额:
$ 41.46万 - 项目类别:
Alpha Emitter Labeled Anti-T Cell Antibody: Targeting Latent HIV Infected Cells
Alpha 发射体标记的抗 T 细胞抗体:针对潜伏的 HIV 感染细胞
- 批准号:
8842434 - 财政年份:2014
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$ 41.46万 - 项目类别:
Alpha Radioimmunotherapy for Lymphoma Treatment
淋巴瘤治疗的阿尔法放射免疫疗法
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8782611 - 财政年份:2013
- 资助金额:
$ 41.46万 - 项目类别:
Alpha Radioimmunotherapy for Lymphoma Treatment
淋巴瘤治疗的阿尔法放射免疫疗法
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8601179 - 财政年份:2013
- 资助金额:
$ 41.46万 - 项目类别:
Allogeneic HCT for Hematologic Malignancies: Immune Manipulations
同种异体 HCT 治疗血液系统恶性肿瘤:免疫操作
- 批准号:
8240005 - 财政年份:2011
- 资助金额:
$ 41.46万 - 项目类别:
Allogeneic HCT for Hematologic Malignancies: Immune Manipulations
同种异体 HCT 治疗血液系统恶性肿瘤:免疫操作
- 批准号:
7585357 - 财政年份:2009
- 资助金额:
$ 41.46万 - 项目类别:
Core--Protocol Management and Coordination of Multi-center Trials
核心--多中心试验的方案管理和协调
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7478453 - 财政年份:2007
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$ 41.46万 - 项目类别:
Core--Protocol Management and Coordination of Multi-center Trials
核心--多中心试验的方案管理和协调
- 批准号:
7304871 - 财政年份:2006
- 资助金额:
$ 41.46万 - 项目类别:
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