EVALUATION OF INVITRO CYTOTOXIC LYMPHOCYTE-T ASSAYS AS A PREDICTIVE TEST FOR THE OCCURRENCE OF GRAFT VS HOST-DISEASE
EVALUATION OF INVITRO CYTOTOXIC LYMPHOCYTE-T ASSAYS AS A PREDICTIVE TEST FOR THE OCCURRENCE OF GRAFT VS HOST-DISEASE
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DOI：
10.1007/bf00215256
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发表时间：
1991-10-01
期刊：
影响因子：
3.2
通讯作者：
PERREAULT, C
中科院分区：
文献类型：
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作者：
FONTAINE, P;LANGLAIS, J;PERREAULT, C
对12种不同程度移植物抗宿主病(GVHD)的小鼠供体组合进行了体外细胞毒性T淋巴细胞(CTL)检测，评价了CTL对异基因骨髓移植后移植物抗宿主病(GVHD)发生的预测价值。这些供体-宿主组合是在对来自6个品系的H-2b小鼠的24个同种异体株组合进行次要组织相容性抗原(MIHA)引发的GVHD评估后选择的。受者(n=475)先前接受全身照射(9.5Gy.)，移植10(7)个骨髓细胞和5×10(7)个脾细胞。虽然在一半的菌株组合中观察到了致死性GVHD，但可以选择12种供体-宿主组合，这些组合的特征是严重的、轻度的或不存在GVHD。在体内启动和体外增强后评估抗宿主CTL活性水平时，无论是否发生GVHD，所有组合都观察到强烈的CTL介导的细胞毒作用。极限稀释法测定的CTL频率为1/16880~1/306。Spearman等级检验显示，无论是在散装培养实验还是在LDA条件下，GVHD强度与供体抗宿主CTL活性之间均不存在正相关。这些结果表明，在体外能够触发有效的CTL反应的MiHA并不一定会引发GVHD，体外检测供体CTL对主体型ConA细胞的活性并不能预测抗MiHA GVHD的方法。然而，针对在造血细胞上特异表达的宿主MIHA的CTL群体的招募的可能性表明了一种治疗血液系统恶性肿瘤的新的治疗策略。事实上，将供者的造血干细胞添加针对宿主造血细胞特异性表达的MIHA的T细胞进行移植，可能会增强理想的移植物抗白血病效果，而不会增加GVHD的风险。
The potential value of in vitro cytotoxic T lymphocyte (CTL) assays for predicting the occurrence of graft vs host disease (GVHD) following allogeneic bone marrow transplantation was evaluated in 12 mouse donor-host combinations associated with various degrees of GVHD. These donor-host combinations were selected after evaluation of GVHD triggered by minor histocompatibility antigens (MiHA) in 24 allogeneic strain combinations derived from six strains of H-2b mice. Recipients (n = 475), previously submitted to total body irradiation (9.5 Gy), were transplanted with 10(7) bone marrow cells along with 5 x 10(7) spleen cells. While lethal GVHD was observed in half of the strain combinations, it was possible to select 12 donor-host combinations characterized by severe, mild, or absent GVHD. When levels of anti-host CTL activity were assessed following in vivo priming and in vitro boosting, strong CTL-mediated cytotoxicity was observed in all combinations whether they developed GVHD or not. CTL frequency measured by limiting dilution analysis (LDA) ranged from 1/16880-1/306. The Spearman rank test revealed no positive correlation between GVHD intensity and donor anti-host CTL activity assayed either in bulk culture experiments or in LDA conditions. These results indicate that MiHA capable of triggering potent CTL responses in vitro do not necessarily initiate GVHD, and that in vitro measurement of donor CTL activity against host-type Con A blasts is not a predictive assay for anti-MiHA GVHD. However, the possibility to recruit CTL populations targeting host MiHA expressed specifically on hematopoietic cells suggests a novel therapeutic strategy for the cure of hematopoietic malignancies. Indeed, transplantation of donor hematopoietic stem cells supplemented with T cells aimed at MiHA specifically expressed by host hematopoietic cells, could possibly potentiate the desirable graft vs leukemia effect without increasing the risk of GVHD.