Autologous and Allogeneic T Cell Strategies for the Treatment of Hematologic Mal

在异基因骨髓移植(AllBMT)中，供者T细胞介导有益的移植物抗白血病(GVL)效应，防止骨髓排斥反应；然而，供者T细胞也可引起移植物抗宿主病(GVHD)。我们已经证实，Tc2表型的供者CD8+T细胞主要通过穿孔素途径介导靶细胞裂解，分泌II型细胞因子，能够通过有限的GVHD介导GVL效应和预防骨髓排斥反应。目前正在评估这种Tc2细胞在非清髓性异基因骨髓移植小鼠模型中的应用。此外，评估捐赠者Tc2细胞在人类异体骨髓移植环境中的作用的试点临床试验正在进行中。这项工作的总体目标是提高allBMT的抗白血病效果，降低GVHD相关的发病率和死亡率，并将allBMT的应用扩大到那些缺乏匹配供者的患者。在自身设置中，T细胞也可能在介导抗白血病效应中发挥作用。正在开发小鼠模型来评估Fas细胞溶解途径在T细胞介导的同基因GVL效应中的作用。此外，对CLL患者的研究正在评估I型和II型细胞因子在Fas途径中对CLL细胞利用的不同作用。这些小鼠和临床前人类研究可能为调节Fas途径治疗白血病提供基础。此外，我们还开发了从外周T细胞群中清除CLL细胞的方法。评估这种自体T细胞是否可以改善基于嘌呤类似物的化疗后的免疫恢复的方案正在开发中。

In the setting of allogeneic bone marrow transplantation (alloBMT), donor T cells mediate a beneficial graft-versus-leukemia (GVL) effect and prevent marrow rejection; however, donor T cells can also generate graft-versus-host disease (GVHD). We have identified that donor CD8+ T cells of Tc2 phenotype, defined by their secretion of type II cytokines and their mediation of target cell lysis primarily via the perforin pathway, are capable of mediating a GVL effect and preventing marrow rejection with limited GVHD. Current efforts are evaluating the use of such Tc2 cells in murine models of non-myeloablative alloBMT. In addition, pilot clinical trials evaluating the effect of donor Tc2 cells in the setting of human alloBMT are being developed. The overall goal of this work is to improve the anti-leukemic effects of alloBMT, to reduce the morbidity and mortality associated with GVHD, and to extend the application of alloBMT to those patients lacking an HLA-matched donor.In the autologous setting, T cells may also play a role in mediating anti-leukemic effects. Murine models are being developed to evaluate the role of the fas cytolytic pathway in T cell-mediated syngeneic GVL effects. In addition, studies in CLL patients are evaluating the differential role of type I versus type II cytokines on CLL cell utilization of the fas pathway. These murine and pre-clinical human studies may provide a basis for modulation of the fas pathway for the treatment of leukemia. In addition, we have developed methodologies to purge CLL cells from peripheral T cell populations. Protocols to evaluate whether such autologous T cells might improve immune recovery after purine analog-based chemotherapy are being developed.