Martin P J
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
Blood. 1996 Aug 1;88(3):962-9.
Clinical trials and experimental studies have demonstrated that donor T cells can play a critical role in preventing allogeneic marrow graft rejection. Results of a previous study showed that donor T cells were most effective for preventing rejection when they recognize an alloantigen expressed by recipient T cells and can cause graft-versus-host disease (GVHD). The present study examined models where marrow graft rejection can be prevented by donor T cells that do not recognize host alloantigens and cannot cause GVHD. Donor T cells prevented rejection of major histocompatibility complex (MHC) class I and II-disparate F1 marrow in parental recipients prepared with > or = 800 cGy total body irradiation (TBI) but not in those prepared with < or = 750 cGy TBI. In recipients prepared with high TBI exposures, rejection was mediated entirely by host CD8 cells. With lower TBI exposures, rejection was mediated by host CD4 cells and CD8 cells. These observations suggested the hypothesis that donor T cells prevent rejection mediated by host effectors that recognize donor MHC class I alloantigens but do not prevent rejection mediated by host effectors that recognize donor class II alloantigens. Consistent with this hypothesis, further experiments showed that F1 donor T cells can prevent rejection of MHC class I-disparate marrow in irradiated parental recipients but have no detectable effect on rejection of MHC class II-disparate marrow. We propose that the expression of MHC class I molecules on donor T cells makes it possible for these cells to inactivate the host response against donor class I alloantigens through a veto mechanism, whereas the absence of MHC class II molecules on murine T cells explains why these cells cannot inactivate the host response against donor class II alloantigens. Finally, donor CD4 cells and CD8 cells were equivalently effective for preventing rejection of F1 marrow in parental recipients, suggesting that veto activity is not restricted solely to the CD8 subset of murine T cells. A veto mechanism could enable donor T cells to prevent allogeneic marrow graft rejection without causing GVHD.
临床试验和实验研究表明，供体T细胞在预防异基因骨髓移植排斥反应中可发挥关键作用。先前一项研究的结果显示，当供体T细胞识别受体T细胞表达的同种异体抗原并可引发移植物抗宿主病（GVHD）时，其在预防排斥反应方面最为有效。本研究检测了一些模型，在这些模型中，不识别宿主同种异体抗原且不会引发GVHD的供体T细胞能够预防骨髓移植排斥反应。供体T细胞可预防经全身照射（TBI）剂量≥800 cGy预处理的亲代受体中主要组织相容性复合体（MHC）I类和II类不相合的F1骨髓的排斥反应，但不能预防经TBI剂量≤750 cGy预处理的亲代受体中F1骨髓的排斥反应。在经高剂量TBI预处理的受体中，排斥反应完全由宿主CD8细胞介导。在较低剂量TBI预处理的受体中，排斥反应由宿主CD4细胞和CD8细胞介导。这些观察结果提示了这样一个假说，即供体T细胞可预防由识别供体MHC I类同种异体抗原的宿主效应细胞介导的排斥反应，但不能预防由识别供体II类同种异体抗原的宿主效应细胞介导的排斥反应。与此假说一致，进一步的实验表明，F1供体T细胞可预防经照射的亲代受体中MHC I类不相合骨髓的排斥反应，但对MHC II类不相合骨髓的排斥反应无明显影响。我们提出，供体T细胞上MHC I类分子的表达使得这些细胞能够通过否决机制使宿主针对供体I类同种异体抗原的反应失活，而鼠T细胞上缺乏MHC II类分子则解释了为什么这些细胞不能使宿主针对供体II类同种异体抗原的反应失活。最后，供体CD4细胞和CD8细胞在预防亲代受体中F1骨髓的排斥反应方面同样有效，这表明否决活性并非仅局限于鼠T细胞的CD8亚群。否决机制可使供体T细胞预防异基因骨髓移植排斥反应而不引发GVHD。
