Minor histocompatibility antigen-specific cytotoxic T lymphocytes generated with dendritic cells from DLA-identical littermates
Minor histocompatibility antigen-specific cytotoxic T lymphocytes generated with dendritic cells from DLA-identical littermates
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DOI：
10.1053/bbmt.2003.50023
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发表时间：
2003-04-01
影响因子：
4.3
通讯作者：
Nash, RA
中科院分区：
文献类型：
--
作者：
Georges, GE;Lesnikova, M;Nash, RA
在主要组织相容性复合体完全相同的异基因造血干细胞移植中，供者特异性细胞毒性T淋巴细胞（CTL）介导移植物抗宿主效应，而宿主特异性CTL介导移植物排斥反应。开发一种可以分离mHA特异性CTL的大型动物模型将加速临床研究中的转化，以改善对移植物抗宿主效应的控制以及预防致敏宿主中的移植物排斥。目标;本研究的目的是从移植前白细胞抗原相同的同窝未致敏受者、稳定的混合造血嵌合体和移植排斥后对mHA致敏的犬中分离mHA特异性CTL。从骨髓来源的CD 34（+）细胞培养供体树突状细胞（DC），并在CTL培养的第1、10和20天用于刺激受体T淋巴细胞。我们可靠地产生和扩大mHA特异性CTL离体致敏狗，给予供体特异性输血，以提高非清髓性移植后移植物排斥反应后的免疫回忆。通过Cr-51释放试验测量的mHA特异性细胞毒性从致敏外周血单核细胞的起始群体中的小于5%富集至CTL培养4周后的中位数63%。扩增的mHA特异性CTL不是组织特异性的：造血细胞、成纤维细胞和造口细胞系以mHA特异性方式裂解。同种异体树突状细胞，而不是外周血单核细胞，刺激mHA特异性CTL的体外扩增是必要的。我们不能从移植前未致敏的狗，从以前致敏的狗，但没有最近的回忆免疫，或从稳定的混合造血嵌合体产生mRA特异性CTL。我们的结论是，最近在体内致敏后，大规模的mRA特异性CTL的体外扩增是可行的，使用同种异体DC。(C)2003年美国血液和骨髓移植学会。
Donor cytotoxic T lymphocytes (CTL) specific for minor histocompatibility antigens (mHA) mediate the graft-versus-host effect whereas host mHA-specific CTL mediate graft rejection in the setting of major histocompatibility complex identical allogeneic hematopoietic stem cell transplantation. Development of a large animal model from which mHA-specific CTL can be isolated would accelerate translation in clinical studies to improve control of the graft-versus-host effect as well as prevention of graft rejection in sensitized hosts. The aims; of the current study were to isolate mHA-specific CTL from dog leukocyte antigen-identical littermate nonsensitized recipients before transplantation, from stable mixed hematopoietic chimeras, and from dogs sensitized to mHA after graft rejection. Donor dendritic cells (DCs) were cultured from bone marrow-derived CD34(+) cells and were used to stimulate recipient T lymphocytes on days 1, 10, and 20 of CTL culture. We reliably generated and expanded mHA-specific CTL ex vivo from sensitized dogs that were given a donor-specific blood transfusion to boost immune recall after graft rejection after a nonmyeloablative transplantation. The mHA-specific cytotoxicity measured by Cr-51 release assay was enriched from less than 5 % in the starting population of sensitized peripheral blood mononuclear cells to a median of 63% after 4 weeks in CTL culture. The expanded mHA-specific CTLs were not tissue-specific: hematopoietic cells, fibroblast, and stomal cell lines were lysed in an mHA-specific manner. Allogeneic DCs, but not peripheral blood mononuclear cells, were necessary for stimulating ex vivo expansion of mHA-specific CTL. We were unable to generate mRA-specific CTL from nonsensitized dogs before transplantation, from previously sensitized dogs but without recent recall immunization, or from stable mixed hematopoietic chimeras. We conclude that after recent in vivo sensitization, large-scale ex vivo expansion of mRA-specific CTL was feasible using allogeneic DCs. (C) 2003 American Society for Blood and Marrow Transplantation.