Riddell Stanley R, Murata M, Bryant S, Warren E H
Fred Hutchinson Cancer Research Center and University of Washington, Seattle, USA.
Int J Hematol. 2002 Aug;76 Suppl 2:155-61. doi: 10.1007/BF03165108.
Immune-mediated elimination of tumor cells by donor T cells recognizing recipient minor H antigens contributes to the curative potential of allogeneic HCT. The importance of the allogeneic response to a successful outcome is clearly illustrated by the results of stem cell transplant for malignancy after nonmyeloablative conditioning. Remarkably little is understood about the molecular nature of minor H antigens and this has impeded efforts to determine the role of specific disparities in graft versus tumor reactions or to manipulate T cell responses to augment antitumor activity without exacerbating GVHD. The isolation of minor H antigen-specific CD8+ and CD4+ T cell clones from recipients of allogeneic HCT has provided the reagents to characterize their expression on leukemic progenitors and to identify the genes encoding these antigens. Using cDNA expression cloning, genetic polymorphisms in the human IFI-75, Uty, KIAA0020, and UGT2B17 genes have been identified to encode new minor H antigens presented by HLA A3, B8, A2, and A29 respectively. Two of these genes are preferentially expressed in hematopoietic cells including leukemic progenitors suggesting it may be possible to augment T cell responses to promote a selective graft versus leukemia effect. A third gene, UGT2B17 is highly expressed in liver and GI tract and may be a target for GVHD in these organs. The studies to identify the molecular nature of minor H antigens have provided insights into the complexities of the graft versus host response associated with allogeneic HCT, but the challenge for the future will be to develop strategies that can selectively induce durable graft versus tumor effects without GVHD. A critical issue in developing specific immunotherapy to augment GVL responses is to determine which minor H antigens are expressed on leukemic stem cells. Studies using transplantation of human AML into SCID mice have identified a putative leukemic stem cell which is contained in the CD34+ CD38- subset of the blast population and is present in very low frequency (<1/200,000) in blood or bone marrow from AML patents. We have examined the ability of minor H antigen-specific CTL to prevent engraftment of human AML in NOD/SCID mice. These studies show that engraftment of leukemias derived from individuals encoding the minor H antigen can be specifically prevented demonstrating that AML stem cells express minor H antigens and are targets for CTL. One approach to determine directly which minor H antigens can be selectively targeted to induce a GVL effect without GVHD is to adoptively transfer T cell clones of defined specificity and function to patients who relapse after HCT. Studies of this approach are now in progress in acute leukemia and have provided important insights into potential obstacles of T cell therapy for relapsed leukemia after HCT.
供体T细胞识别受体次要组织相容性抗原，通过免疫介导消除肿瘤细胞，这有助于异基因造血细胞移植的治愈潜力。非清髓性预处理后恶性肿瘤干细胞移植的结果清楚地表明了同种异体反应对成功治疗结果的重要性。关于次要组织相容性抗原的分子本质，人们了解得非常少，这阻碍了确定特定差异在移植物抗肿瘤反应中的作用，或在不加重移植物抗宿主病（GVHD）的情况下操纵T细胞反应以增强抗肿瘤活性的努力。从异基因造血细胞移植受者中分离出次要组织相容性抗原特异性CD8+和CD4+T细胞克隆，为表征它们在白血病祖细胞上的表达以及鉴定编码这些抗原的基因提供了试剂。利用cDNA表达克隆技术，已确定人类IFI-75、Uty、KIAA0020和UGT2B17基因中的遗传多态性分别编码由HLA A3、B8、A2和A29呈递的新的次要组织相容性抗原。其中两个基因在包括白血病祖细胞在内的造血细胞中优先表达，这表明有可能增强T细胞反应以促进选择性的移植物抗白血病效应。第三个基因UGT2B17在肝脏和胃肠道中高度表达，可能是这些器官中移植物抗宿主病的靶点。鉴定次要组织相容性抗原分子本质的研究为与异基因造血细胞移植相关的移植物抗宿主反应的复杂性提供了见解，但未来的挑战将是制定能够在不发生移植物抗宿主病的情况下选择性诱导持久的移植物抗肿瘤效应的策略。开发特异性免疫疗法以增强移植物抗白血病反应的一个关键问题是确定哪些次要组织相容性抗原在白血病干细胞上表达。利用将人类急性髓系白血病移植到重症联合免疫缺陷（SCID）小鼠中的研究，已鉴定出一种假定的白血病干细胞，它存在于原始细胞群体的CD34+CD38-亚群中，在急性髓系白血病患者的血液或骨髓中以非常低的频率（<1/200,000）存在。我们已经研究了次要组织相容性抗原特异性细胞毒性T淋巴细胞（CTL）预防人类急性髓系白血病在非肥胖糖尿病/重症联合免疫缺陷（NOD/SCID）小鼠中植入的能力。这些研究表明，编码次要组织相容性抗原的个体来源的白血病植入可以被特异性预防，这表明急性髓系白血病干细胞表达次要组织相容性抗原并且是CTL的靶点。一种直接确定哪些次要组织相容性抗原可以被选择性靶向以诱导移植物抗白血病效应而不发生移植物抗宿主病的方法是将具有明确特异性和功能的T细胞克隆过继转移给造血细胞移植后复发的患者。目前正在对急性白血病进行这种方法的研究，并且已经为造血细胞移植后复发白血病的T细胞治疗的潜在障碍提供了重要见解。
