Johnson B D, Becker E E, Truitt R L
Department of Pediatrics, Medical College of Wisconsin, Milwaukee 53226, USA.
Biol Blood Marrow Transplant. 1999;5(3):123-32. doi: 10.1053/bbmt.1999.v5.pm10392958.
Infusions of donor leukocytes have been given to allogeneic bone marrow recipients after transplant to treat leukemia relapse. Treatment with these delayed infusions of donor cells has been called delayed or donor leukocyte infusion (DLI). While graft-vs.-host disease (GVHD) has typically been less severe than expected after DLI, it still remains a significant risk factor. Recently, we used a full major histocompatibility complex (MHC)-mismatched model (C57BL/6 into AKR) to determine how increased immunogenetic disparity affects GVH and graft-vs.-leukemia (GVL) reactions after DLI. In contrast to an MHC-matched model (B10.BR into AKR), GVHD was still observed when MHC-mismatched donor T cells were infused 3 weeks posttransplant. Limiting dilution analysis was used to determine the frequency of alloreactive cytotoxic T lymphocytes (CTL) and interleukin (IL)-2-secreting T helper cells in the spleens of MHC-mismatched recipients 7 days after DLI treatment. GVHD correlated with elevated frequencies of alloreactive T-helper cells. One strategy for reducing the severity of GVHD after DLI is the selective administration of CD4 or CD8 T-subsets. Delayed infusion of purified T-subsets 3 weeks posttransplant resulted in significantly less GVHD than infusion of a mixture of the two subsets. No GVH-associated mortality was observed after DLI with purified donor CD4+ T cells. In GVL studies, MHC-mismatched CD8+ T cells were the most potent antitumor effectors against an acute T cell leukemia. The GVL effect of MHC-mismatched T-subsets was compared with that of MHC-matched subsets. When naive MHC-matched cells were given as DLI, depletion of either T-subset eliminated the GVL effect. CD8+ T cells from MHC-matched donors primed against host alloantigens, however, mediated a CD4 (T-helper)-independent GVL reaction. Together, these results suggest that administration of T-subsets can significantly reduce GVHD after DLI without loss of the beneficial GVL effect.
移植后，已对异基因骨髓移植受者输注供体白细胞以治疗白血病复发。这种对供体细胞的延迟输注治疗被称为延迟或供体白细胞输注（DLI）。虽然DLI后的移植物抗宿主病（GVHD）通常比预期的要轻，但它仍然是一个重要的风险因素。最近，我们使用了一个完全主要组织相容性复合体（MHC）不匹配的模型（C57BL/6小鼠移植到AKR小鼠）来确定免疫遗传差异增加如何影响DLI后的GVH和移植物抗白血病（GVL）反应。与MHC匹配的模型（B10.BR小鼠移植到AKR小鼠）不同，在移植后3周输注MHC不匹配的供体T细胞时，仍观察到GVHD。采用有限稀释分析法确定DLI治疗7天后MHC不匹配受者脾脏中同种反应性细胞毒性T淋巴细胞（CTL）和分泌白细胞介素（IL）-2的T辅助细胞的频率。GVHD与同种反应性T辅助细胞频率升高相关。降低DLI后GVHD严重程度的一种策略是选择性给予CD4或CD8 T亚群。移植后3周延迟输注纯化的T亚群导致的GVHD明显少于输注这两个亚群的混合物。用纯化的供体CD4+ T细胞进行DLI后未观察到与GVH相关联的死亡。在GVL研究中，MHC不匹配的CD8+ T细胞是针对急性T细胞白血病最有效的抗肿瘤效应细胞。将MHC不匹配的T亚群的GVL效应与MHC匹配的亚群的GVL效应进行了比较。当给予未经致敏的MHC匹配细胞作为DLI时，任一T亚群的耗竭都会消除GVL效应。然而，来自MHC匹配供体的、针对宿主同种抗原致敏的CD8+ T细胞介导了一种不依赖CD4（T辅助）的GVL反应。总之，这些结果表明，给予T亚群可显著降低DLI后的GVHD，而不会丧失有益的GVL效应。
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