Goss J A, Nakafusa Y, Flye M W
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
Ann Surg. 1993 May;217(5):492-9; discussion 499-501. doi: 10.1097/00000658-199305010-00009.
This study determined the form of cellular donor MHC alloantigen necessary for the induction of intrathymic tolerance.
The authors have achieved indefinite donor-specific tolerance, to a fully MHC-disparate rat heterotopic cardiac allograft, after the pretransplant intrathymic injection of unfractionated donor splenocytes and a single injection of rabbit anti-rat lymphocyte serum (ALS), without subsequent immunosuppression.
Male 4-12-week-old Buffalo (RT1b) rats underwent an intrathymic injection of either fractionated Lewis (RT1(1)) red blood cells (purified by Ficoll gradient) or T lymphocytes (purified by nylon wool column and plastic adherence), both of which express only MHC class I alloantigens, or B lymphocytes, macrophages, and dendritic cells (purified by plastic adherence) which express both MHC class I and class II alloantigens. At the completion of alloantigen injection the Buffalo recipient rats were given 1 ml of ALS intraperitoneally. Twenty-one days later a heterotopic Lewis heart was transplanted.
The intrathymic injection of the fractions of Lewis MHC class I and class II expressing B lymphocytes, macrophages, and dendritic cells induced a donor-specific tolerance that resulted in indefinite Lewis cardiac allograft survival (MST > 125 days) in all recipients without further immunosuppression, whereas groups receiving MHC class I expressing red blood cell or T lymphocyte injections plus ALS rejected Lewis cardiac allografts with a MST of 7.3 and 16.5 days, respectively, thus indicating that the MHC class II expressing cell is necessary for the induction of intrathymic tolerance. Buffalo recipients with a long-term surviving Lewis cardiac allograft, after Lewis MHC class II expressing cells were still able to reject a third-party heterotopic ACI (RT1a) cardiac allograft in normal time (MST = 7.0 days), but did not reject a second Lewis cardiac allograft (MST > 100 days). Additionally, the intrathymic injection of MHC class II expressing cells resulted in decreased interleukin-2 (IL-2) production and an 80% decrease in in vitro donor-specific cell mediated cytotoxicity, whereas the cytolytic response to a third party was unaltered.
Donor MHC class II, and not class I, expressing cells are the cells in donor splenocytes, injected intrathymically, responsible for the development of donor-specific allograft tolerance.
本研究确定诱导胸腺内耐受所需的细胞供体MHC同种异体抗原的形式。
在移植前胸腺内注射未分级的供体脾细胞和单次注射兔抗大鼠淋巴细胞血清（ALS）后，作者已实现对完全MHC不相容的大鼠异位心脏同种异体移植的无限期供体特异性耐受，且无需后续免疫抑制。
4至12周龄的雄性布法罗（RT1b）大鼠接受胸腺内注射分级的刘易斯（RT1(1)）红细胞（通过Ficoll梯度纯化）或T淋巴细胞（通过尼龙毛柱和塑料黏附纯化），这两者均仅表达MHC I类同种异体抗原，或注射B淋巴细胞、巨噬细胞和树突状细胞（通过塑料黏附纯化），它们表达MHC I类和II类同种异体抗原。在同种异体抗原注射完成后，给布法罗受体大鼠腹腔内注射1 ml ALS。21天后移植异位刘易斯心脏。
胸腺内注射表达刘易斯MHC I类和II类的B淋巴细胞、巨噬细胞和树突状细胞组分可诱导供体特异性耐受，导致所有受体的刘易斯心脏同种异体移植无限期存活（平均存活时间>125天），无需进一步免疫抑制，而接受表达MHC I类的红细胞或T淋巴细胞注射加ALS的组分别在7.3天和16.5天内排斥刘易斯心脏同种异体移植，这表明表达MHC II类的细胞是诱导胸腺内耐受所必需的。在注射表达刘易斯MHC II类细胞后长期存活刘易斯心脏同种异体移植的布法罗受体，仍能够在正常时间内排斥第三方异位ACI（RT1a）心脏同种异体移植（平均存活时间=7.0天），但不排斥第二次刘易斯心脏同种异体移植（平均存活时间>100天）。此外，胸腺内注射表达MHC II类的细胞导致白细胞介素-2（IL-2）产生减少，体外供体特异性细胞介导的细胞毒性降低80%，而对第三方的细胞溶解反应未改变。
胸腺内注射的供体脾细胞中，表达供体MHC II类而非I类的细胞是负责供体特异性同种异体移植耐受发展的细胞。
