Stadlbauer T H, Schaub M, Magee C C, Kupiec-Weglinski J W, Sayegh M H
Surgical Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Heart Lung Transplant. 2000 Jun;19(6):566-75. doi: 10.1016/s1053-2498(00)00098-x.
Intrathymic injection of alloantigen in the form of donor cells, soluble major histocompatibility complex (MHC) molecules, or MHC allopeptides induces donor-specific tolerance in a variety of acute allograft rejection models. We have previously shown that a single intrathymic injection of donor spleen cells into pre-sensitized rats abrogates accelerated (circa 24-hour) rejection and prolongs the survival of cardiac allografts to about 7 days. The present study was designed to investigate the mechanisms by which intrathymic administration of donor cells modifies the course of accelerated rejection.
Lewis RT1(1) (LEW) rats sensitized by transplantation with Wistar-Furth RT1(u) (WF) skin grafts received WF cardiac allografts 7 days later-a classic model of accelerated rejection. At the time of skin challenge, however, certain animals received intrathymic cell suspensions (either allogeneic or syngeneic) or donor-derived class I and/or class II MHC peptides.
Control animals (sensitized by skin grafts but receiving no other treatment) rejected cardiac allografts within 24 hours. Intrathymic injection of WF splenocytes at the time of skin transplantation abrogated rejection at 24 hours and prolonged cardiac allograft survival to 6.6+/-0.6 days (p<0.001), whereas intrathymic administration of syngeneic (LEW) or allogeneic third party Brown Norway RT1(n) cells was ineffective in this regard. Intrathymic injection of gamma-irradiated donor cells marginally extended cardiac allograft survival to 3.0+/-0.9 days (p< 0.001), but the grafts were still rejected in an accelerated fashion. Intrathymic injection of donor-derived class I and/or class II MHC allopeptides at the same time period also failed to prolong cardiac allograft survival beyond 3 days. In the group receiving unmodified donor cells, elevated immunoglobulin M (IgM) and immunoglobulin G (IgG) allo-antibodies were found at the time of cardiac transplantation; this pattern was not observed with any other treatment.
The superiority of non-modified donor spleen cells over gamma-irradiated donor cells or donor specific allopeptides in modifying the course of accelerated cardiac rejection suggests that direct allorecognition is the dominant pathway initiating rejection in sensitized transplant recipients. Marked alterations in the antidonor IgM and IgG responses are associated with successful abrogation of accelerated rejection by thymic immunomodulatory mechanisms.
以供体细胞、可溶性主要组织相容性复合体（MHC）分子或MHC同种异体肽的形式胸腺内注射同种异体抗原，可在多种急性同种异体移植排斥模型中诱导供体特异性耐受。我们之前已经表明，将供体脾细胞单次胸腺内注射到预先致敏的大鼠体内，可消除加速（约24小时）排斥反应，并将心脏同种异体移植的存活期延长至约7天。本研究旨在探讨胸腺内给予供体细胞改变加速排斥反应进程的机制。
通过移植Wistar-Furth RT1(u)（WF）皮肤移植物致敏的Lewis RT1(1)（LEW）大鼠，7天后接受WF心脏同种异体移植——一种经典的加速排斥模型。然而，在皮肤攻击时，某些动物接受胸腺内细胞悬液（同种异体或同基因）或供体来源的I类和/或II类MHC肽。
对照动物（通过皮肤移植物致敏但未接受其他治疗）在24小时内排斥心脏同种异体移植。在皮肤移植时胸腺内注射WF脾细胞可在24小时消除排斥反应，并将心脏同种异体移植存活期延长至6.6±0.6天（p<0.001），而胸腺内给予同基因（LEW）或同种异体第三方Brown Norway RT1(n)细胞在这方面无效。胸腺内注射γ射线照射的供体细胞可将心脏同种异体移植存活期略微延长至3.0±0.9天（p<0.001），但移植物仍以加速方式被排斥。在同一时期胸腺内注射供体来源的I类和/或II类MHC同种异体肽也未能将心脏同种异体移植存活期延长超过3天。在接受未修饰供体细胞的组中，心脏移植时发现免疫球蛋白M（IgM）和免疫球蛋白G（IgG）同种异体抗体升高；其他任何治疗均未观察到这种模式。
在改变加速心脏排斥反应进程方面，未修饰的供体脾细胞优于γ射线照射的供体细胞或供体特异性同种异体肽，这表明直接同种异体识别是致敏移植受者中引发排斥反应的主要途径。抗供体IgM和IgG反应的显著改变与胸腺免疫调节机制成功消除加速排斥反应相关。
