Terness P, Dufter C, Otto G, Opelz G
Department of Transplantation Immunology, University of Heidelberg, Germany.
Transpl Int. 1996;9(1):2-8. doi: 10.1007/BF00336805.
T cells recognize foreign antigens in the form of peptide fragments resulting from antigen processing by antigen-presenting cells. In contrast to this indirect recognition, MHC molecules of foreign cells can be directly recognized by T cells. Direct recognition has for a long time been considered the only mechanism responsible for transplant rejection. Recent studies have provided evidence of a role of indirect recognition in rejection. In the current series of experiments, we studied the influence of indirect alloactivation, induced either by donor MHC class I peptides or by membrane-bound MHC I molecules, on heart allograft rejection in rats. Recipients were immunized before transplantation with synthetic donor MHC I peptides. The animals developed antibody and T-cell responses. Depending on the rat strain, peptide pretreatment either had no effect on graft survival (DA-->PVG; untreated controls 8.5 +/- 0.6 days, treated rats 9.5 +/- 0.6 days) or led to accelerated rejection (DA-->LEW; untreated controls 7.5 +/- 0.3 days, treated rats 5.1 +/- 0.2 days; P < 0.0002). Importantly, sensitization by indirect activation induced acute rejection in a donor-recipient combination (LEW.1A-->LEW.1WR2) in which neither direct nor indirect recognition led to rejection (untreated controls > 400 days, pretreated rats 15 +/- 4.2 days). Another group of animals was immunized with allogeneic or congenic erythrocytes carrying the MHC I antigen from which the peptides were derived. Although the immunization elicited a measurable immune response, it did not lead to accelerated rejection. We conclude that sensitization by indirect recognition is able to initiate an acute rejection even in recipients in which neither direct nor indirect recognition is effective, and that this effect is strain-dependent. The form in which the donor antigen is administered is decisive for the induction of rejection by indirect activation.
T细胞以抗原呈递细胞对抗原进行加工后产生的肽片段形式识别外来抗原。与这种间接识别不同，外来细胞的MHC分子可被T细胞直接识别。长期以来，直接识别一直被认为是导致移植排斥的唯一机制。最近的研究提供了间接识别在排斥反应中起作用的证据。在当前这一系列实验中，我们研究了由供体MHC I类肽或膜结合MHC I分子诱导的间接同种异体激活对大鼠心脏同种异体移植排斥反应的影响。受体在移植前用合成的供体MHC I肽进行免疫。这些动物产生了抗体和T细胞反应。根据大鼠品系的不同，肽预处理要么对移植物存活没有影响（DA→PVG；未处理的对照组为8.5±0.6天，处理后的大鼠为9.5±0.6天），要么导致排斥反应加速（DA→LEW；未处理的对照组为7.5±0.3天，处理后的大鼠为5.1±0.2天；P<0.0002）。重要的是，间接激活致敏在一个供体-受体组合（LEW.1A→LEW.1WR2）中诱导了急性排斥反应，在该组合中，直接识别和间接识别均未导致排斥反应（未处理的对照组>400天，预处理后的大鼠为15±4.2天）。另一组动物用携带肽所源自的MHC I抗原的同种异体或同基因红细胞进行免疫。尽管这种免疫引发了可测量的免疫反应，但并未导致排斥反应加速。我们得出结论，间接识别致敏即使在直接识别和间接识别均无效的受体中也能够引发急性排斥反应，并且这种效应是品系依赖性的。供体抗原的给药形式对于间接激活诱导排斥反应起决定性作用。
