Tremblay N, Fontaine P, Perreault C
Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
Transplantation. 1994 Jul 15;58(1):59-67.
Minor histocompatibility antigens (MiHA) may represent ideal targets for cancer immunotherapy since (1) the expression of many MiHA is tissue specific and (2) they can trigger potent T lymphocyte responses. A primary objective of our research program is to characterize T cell responses to cells displaying multiple incompatible MiHA. Early in the course of this work, we observed in various stimulator/responder combinations that immunization versus multiple MiHA generated cytotoxic effectors that killed not only stimulator cells but also a large panel of MHC-identical and MHC-different targets. To characterize the cells responsible for this cytotoxic activity and their specificity, we expanded polyclonal and clonal CD3+ CD4- CD8+ LP anti-C57BL/6 effectors. LP anti-C57BL/6 polyclonal effectors (LPTc cell line) showed strong cytotoxic activity when tested against several H-2b and non-H-2b targets, but displayed, respectively, weak or absent cytotoxicity against MHC class I-deficient cells and syngeneic cells. When used as cold targets, C57BL/6 cells inhibited the lysis of all H-2b and non-H-2b cells. Some H-2b, but no H-2d or H-2k, cold targets inhibited the lysis of C57BL/6 targets. With the exception of LP and C57BL/6, all types of H-2b cells (A.BY, D1.LP and C3H.SW) showed complete reciprocal inhibition of lysis. The same observation was made for non-H-2b targets. The cytotoxicity profile of 12/14 LP anti-C57BL/6 clones was identical to that of the LPTc cell line, while 2/14 clones recognized only H-2b cells. Cytotoxicity was inhibited by incubation of effector cells with anti-CD3 or anti-CD8 antibodies and by incubation of target cells with specific anti-MHC class I antibodies. These results show that immunization against multiple MiHA in the context of self-MHC generates 2 types of CTL: some are strictly self-MHC restricted while others are strongly cross-reactive and recognized MHC-peptide complexes on allogeneic MHC-different targets. This observation has significant implications concerning the use of anti-MiHA T cells in cancer immunotherapy.
次要组织相容性抗原（MiHA）可能是癌症免疫治疗的理想靶点，因为：（1）许多MiHA的表达具有组织特异性；（2）它们能触发强烈的T淋巴细胞反应。我们研究项目的一个主要目标是表征T细胞对展示多种不相容MiHA的细胞的反应。在这项工作的早期，我们在各种刺激细胞/反应细胞组合中观察到，针对多种MiHA进行免疫会产生细胞毒性效应细胞，这些效应细胞不仅能杀死刺激细胞，还能杀死一大批MHC相同和MHC不同的靶细胞。为了表征负责这种细胞毒性活性的细胞及其特异性，我们扩增了多克隆和克隆的CD3 + CD4 - CD8 + LP抗C57BL/6效应细胞。LP抗C57BL/6多克隆效应细胞（LPTc细胞系）在针对几种H-2b和非H-2b靶细胞进行测试时表现出强大的细胞毒性活性，但对MHC I类缺陷细胞和同基因细胞分别表现出微弱或无细胞毒性。当用作冷靶细胞时，C57BL/6细胞抑制所有H-2b和非H-2b细胞的裂解。一些H-2b冷靶细胞，但没有H-2d或H-2k冷靶细胞，抑制C57BL/6靶细胞的裂解。除了LP和C57BL/6之外，所有类型的H-2b细胞（A.BY、D1.LP和C3H.SW）都表现出完全相互抑制裂解。对非H-2b靶细胞也有相同的观察结果。12/14的LP抗C57BL/6克隆的细胞毒性谱与LPTc细胞系相同，而2/14的克隆仅识别H-2b细胞。效应细胞与抗CD3或抗CD8抗体孵育以及靶细胞与特异性抗MHC I类抗体孵育可抑制细胞毒性。这些结果表明，在自身MHC背景下针对多种MiHA进行免疫会产生两种类型的CTL：一些严格受自身MHC限制，而另一些具有强烈的交叉反应性，能识别异基因MHC不同靶细胞上的MHC - 肽复合物。这一观察结果对于在癌症免疫治疗中使用抗MiHA T细胞具有重要意义。
