Young Kevin J, Kay Lyndsey S, Phillips M James, Zhang Li
Department of Laboratory Medicine and Pathobiology, Multi Organ Transplantation Program, Toronto General Research Institute, University Health Network, 621 University Avenue, Toronto, Ontario M5G 2C4, Canada.
Cancer Res. 2003 Nov 15;63(22):8014-21.
Allogeneic lymphocytes are potent mediators of leukemia and lymphoma remission. The goal of this study was to determine whether single MHC class I locus-mismatched lymphocytes could generate an antilymphoma activity in the absence of graft-versus-host-disease (GVHD) and to understand the underlying mechanisms. Immunoincompetent Scid or lethally irradiated mice were challenged i.v. with a lethal dose of A20 lymphoma cells together with an infusion of single MHC class I locus mismatched splenocytes. Mice that were challenged with A20 cells alone succumbed to lymphoma between 34 and 50 days after infusion. In contrast, >75% of mice that were coinfused with single class I MHC locus mismatched splenocytes survived indefinitely (n = 20) in the absence of GVHD. Interestingly, the number of CD3(+)CD4(-)CD8(-) double-negative (DN) T cells increased 15-fold in mice that did not develop lymphoma. Both DN T cells isolated from the spleens of lymphoma-free mice and DN T cells cloned from naïve mice were cytotoxic to A20 lymphoma cells in vitro. When DN T cell clones were infused into naïve mice i.v. together with A20 lymphoma cells, 86% of recipient mice were protected from lymphoma onset and did not develop GVHD (n = 22). To assess whether the systemic injection of DN T cells can also suppress local tumor development, A20 cells were infused i.m., and at the same time DN T cell clones were infused either i.v. or i.m. Results indicated that DN T cells infused systemically (i.v.) could not prevent local tumor outgrowth, but DN T cells coinfused locally (i.m.) prevented local tumor development in 91% of animals (n = 11). Furthermore, we demonstrate that primary DN T cells were also able to prevent tumor growth in 75% of mice when infused together with A20 cells i.m. (n = 12). Together, these results demonstrate that an antilymphoma activity can be generated in mice without causing GVHD. Furthermore, DN T cells can suppress lymphoma cells in vivo and in vitro, suggesting that DN T cells could be used as a novel strategy for the treatment of lymphoma.
同种异体淋巴细胞是白血病和淋巴瘤缓解的有效介质。本研究的目的是确定单个MHC I类基因座不匹配的淋巴细胞在无移植物抗宿主病（GVHD）的情况下是否能产生抗淋巴瘤活性，并了解其潜在机制。免疫缺陷的Scid小鼠或经致死剂量照射的小鼠经静脉注射致死剂量的A20淋巴瘤细胞，并输注单个MHC I类基因座不匹配的脾细胞。单独用A20细胞攻击的小鼠在输注后34至50天内死于淋巴瘤。相比之下，超过75%的同时输注单个I类MHC基因座不匹配脾细胞的小鼠在无GVHD的情况下无限期存活（n = 20）。有趣的是，未发生淋巴瘤的小鼠中CD3(+)CD4(-)CD8(-)双阴性（DN）T细胞数量增加了15倍。从无淋巴瘤小鼠脾脏中分离的DN T细胞和从幼稚小鼠中克隆的DN T细胞在体外对A20淋巴瘤细胞均具有细胞毒性。当将DN T细胞克隆与A20淋巴瘤细胞一起经静脉注射到幼稚小鼠体内时，86%的受体小鼠免受淋巴瘤发作且未发生GVHD（n = 22）。为了评估全身注射DN T细胞是否也能抑制局部肿瘤发展，将A20细胞经肌肉注射，同时将DN T细胞克隆经静脉或肌肉注射。结果表明，全身（经静脉）注射的DN T细胞不能阻止局部肿瘤生长，但局部（经肌肉）共同注射的DN T细胞在91%的动物中（n = 11）阻止了局部肿瘤发展。此外，我们证明，当与A20细胞一起经肌肉注射时，原代DN T细胞也能在75%的小鼠中（n = 12）阻止肿瘤生长。总之，这些结果表明，在小鼠中可以产生抗淋巴瘤活性而不引起GVHD。此外，DN T细胞在体内和体外均可抑制淋巴瘤细胞，提示DN T细胞可作为治疗淋巴瘤的新策略。
