Zeis M, Uharek L, Hartung G, Glass B, Steinmann J, Schmitz N
2nd Department of Internal Medicine, University of Kiel, Kiel, Germany.
Hematol J. 2001;2(2):136-44. doi: 10.1038/sj/thj/6200087.
The transfer of allogeneic lymphocytes contained in a hematopoietic stem cell graft confers an immune-mediated antileukemic effect, termed the graft-vs-leukemia (GVL) effect. Graft-vs-host disease (GVHD), the most detrimental complication of allogeneic BMT, largely resides within the same lymphocyte population. Therefore, separation of GVL- and GVH-reactions is a long-standing goal of experimental studies dealing with allogeneic transplantation of hematopoietic stem cells.
The objective of the current study was to assess the potential of Th1- and Th2-type CD4+ T cells in mediating GVHD and GVL effects in a fully allogeneic murine transplant model. BALB/c (H-2d) mice were given a dose of A20 (H-2d, B-cell leukemia) cells two days prior to lethal total body irradiation (TBI) and transplantation of fully mismatched (C57BL/6, H-2b) T-cell depleted (anti-Thy1.2, CD90) bone marrow (TCD-BM) cells. Graded numbers of either unmanipulated, Th1- or Th2-polarized highly enriched CD4+ donor type T cells (10(6) or 10(7)) were administered 2 h posttransplant. Infusion of 10(6) of unmanipulated, Th1-, or Th2-primed CD4+ T cells resulted in moderate GVHD-related mortality (40%, 50%, 10%) and significantly improved long-term survival (50%, 45%, 46% surviving the observation period of 120 days) as compared to animals receiving TCD-BM alone (18%).
The administration of 10(7) unmanipulated or Th1-type CD4+ T cells given shortly after transplantation led to death of all mice within 50 days due to fatal acute GVHD. In contrast, the adoptive transfer of 10(7) Th2-primed CD4+ T cells resulted in significant improvement of long-term survival (80%) compared to the TCD-BM group. This powerful GVL effect was associated with a substantially lower incidence of lethal acute GVHD (10%) if compared to the results of transplantation of Th1-type CD4+ T cells.
These results demonstrate that allogeneic Th2-type CD4+ T cells given post BMT can induce GVL effects in a cell-dose-dependent manner without increasing the risk of severe acute GVHD.
造血干细胞移植中所含的同种异体淋巴细胞转移可产生免疫介导的抗白血病效应，称为移植物抗白血病（GVL）效应。移植物抗宿主病（GVHD）是同种异体骨髓移植最有害的并发症，主要存在于相同的淋巴细胞群体中。因此，分离GVL反应和GVH反应是造血干细胞同种异体移植实验研究的长期目标。
本研究的目的是评估在完全同种异体小鼠移植模型中，Th1型和Th2型CD4 + T细胞介导GVHD和GVL效应的潜力。在致死性全身照射（TBI）和移植完全不匹配（C57BL / 6，H-2b）T细胞清除（抗Thy1.2，CD90）骨髓（TCD-BM）细胞前两天，给BALB / c（H-2d）小鼠注射一剂A20（H-2d，B细胞白血病）细胞。移植后2小时给予分级数量的未处理、Th1或Th2极化的高度富集的CD4 +供体类型T细胞（10^6或10^7）。与仅接受TCD-BM的动物（18％）相比，输注10^6未处理、Th1或Th2预刺激的CD4 + T细胞导致中度GVHD相关死亡率（40％，50％，10％），并显著提高长期存活率（50％，45％，46％在120天观察期内存活）。
移植后不久给予10^7未处理或Th1型CD4 + T细胞导致所有小鼠在50天内死于致命的急性GVHD。相比之下，与TCD-BM组相比，过继转移10^7 Th2预刺激的CD4 + T细胞可显著提高长期存活率（80％）。与Th1型CD4 + T细胞移植结果相比，这种强大的GVL效应与致死性急性GVHD的发生率显著降低（10％）相关。
这些结果表明，骨髓移植后给予同种异体Th2型CD4 + T细胞可以以细胞剂量依赖性方式诱导GVL效应，而不会增加严重急性GVHD的风险。
