Fowler D H, Gress R E
National Cancer Institute, Department of Experimental Transplantation and Immunology, Bethesda, MD, USA.
Leuk Lymphoma. 2000 Jul;38(3-4):221-34. doi: 10.3109/10428190009087014.
Allogeneic stem cell transplantation (SCT) represents a curative treatment option for patients with leukemia and lymphoma. T lymphocytes contained in the allograft mediate a graft-versus-leukemia (GVL) effect and prevent graft rejection; however, T cells also initiate graft-versus-host disease (GVHD). Identification of T cell populations which mediate a GVL effect and prevent rejection with reduced GVHD will likely improve transplantation outcome. T cells exist in four functionally-defined populations, the CD4+, Th1/Th2 and CD8+, Tc1/Tc2 subsets. Th1-type CD4 cells primarily secrete type I cytokines (IL-2 and IFN-gamma), whereas Th2 cells secrete type II cytokines (IL-4, IL-5, and IL-10). Similarly, the CD8+ Tc1 and Tc2 cells differentially secrete the type I and type II cytokines, respectively. In addition to cytokine secretion, Tc1 and Tc2 populations mediate cytolytic effects, with Tc1 cells utilizing both perforin- and fas-based killing pathways, whereas Tc2 cells primarily utilize perforin-mediated cytolysis. In murine transplantation models of graft rejection, GVHD, and GVL effects, we have evaluated such functional T cell subsets for their ability to differentially mediate and regulate transplantation responses. These studies demonstrate that donor Th2 cells do not initiate acute GVHD, and can regulate the GVHD mediated by unmanipulated donor T cells without impairing alloengraftment. Additional experiments have shown that allospecific donor Tc2 cells result in reduced GVHD, and mediate a significant GVL effect. Thirdly, we have demonstrated that non-host reactive Tc2 cells with veto-like activity can potently abrogate marrow rejection independent of GVHD. Together, these results demonstrate that functionally-defined donor Th2 and Tc2 populations play an important role in the regulation of GVHD, the prevention of graft rejection, and the mediation of GVL effects, and suggest that utilization of Th2 and Tc2 cells in clinical allogeneic SCT may have potential for improving treatment outcome.
异基因干细胞移植（SCT）是白血病和淋巴瘤患者的一种治愈性治疗选择。同种异体移植物中所含的T淋巴细胞介导移植物抗白血病（GVL）效应并防止移植物排斥；然而，T细胞也会引发移植物抗宿主病（GVHD）。鉴定介导GVL效应并防止排斥且降低GVHD的T细胞群体可能会改善移植结果。T细胞存在于四个功能定义的群体中，即CD4 +、Th1/Th2和CD8 +、Tc1/Tc2亚群。Th1型CD4细胞主要分泌I型细胞因子（IL-2和IFN-γ），而Th2细胞分泌II型细胞因子（IL-4、IL-5和IL-10）。同样，CD8 + Tc1和Tc2细胞分别差异分泌I型和II型细胞因子。除了细胞因子分泌外，Tc1和Tc2群体介导细胞溶解作用，Tc1细胞利用穿孔素和基于Fas的杀伤途径，而Tc2细胞主要利用穿孔素介导的细胞溶解作用。在移植物排斥、GVHD和GVL效应的小鼠移植模型中，我们评估了这些功能性T细胞亚群差异介导和调节移植反应的能力。这些研究表明，供体Th2细胞不会引发急性GVHD，并且可以调节未处理的供体T细胞介导的GVHD，而不会损害同种异体植入。额外的实验表明，同种异体特异性供体Tc2细胞可降低GVHD，并介导显著的GVL效应。第三，我们已经证明具有否决样活性的非宿主反应性Tc2细胞可以有效地消除骨髓排斥，而与GVHD无关。总之，这些结果表明，功能定义的供体Th2和Tc2群体在GVHD的调节、移植物排斥的预防和GVL效应的介导中发挥重要作用，并表明在临床异基因SCT中利用Th2和Tc2细胞可能具有改善治疗结果的潜力。
