Arima T, Goss J A, Walp L A, Flye M W
Department of Surgery, Washington University School of Medicine, St. Louis, Mo., USA.
Surgery. 1995 Aug;118(2):265-72; discussion 272-3. doi: 10.1016/s0039-6060(05)80333-2.
We have previously reported the induction of donor-specific tolerance to cardiac allografts after intrathymic injection of alloantigen with simultaneous administration of antilymphocyte serum treatment to eliminate peripheral T cells. The present study determines whether prolongation of a fully major histocompatibility complex-mismatched cardiac allograft is achieved after a single administration of anti-CD4 monoclonal antibody (MoAb) combined with intrathymic injection of alloantigen.
Male Buffalo rats were given Lewis splenocytes via the intrathymic or intravenous route in combination with a single administration of anti-CD4 monoclonal antibody (OX-38) or anti-CD8 MoAb (OX-8) or both. Heterotopic cardiac transplantation was performed 21 days after intrathymic alloantigen or MoAb pretreatment or both. Fluorescence-activated cell sorter analysis determined changes in lymphocyte compartment T-cell subsets, and in vitro studies examined recipient cellular reactivity.
By 21 days after anti-CD4 MoAb treatment earlier nonspecific immunosuppression had resolved with 80% recovery of peripheral CD4+ T cells and restoration of recipient immunocompetence to allow normal rejection of a cardiac allograft. Combined treatment with intrathymic, but not intravenous, alloantigen plus anti-CD4 MoAb induced donor-specific tolerance to subsequent rat cardiac allografts. However, anti-CD8 MoAb combined with intrathymic alloantigen failed to induce tolerance despite a profound depletion of the CD8+ T-cell subset.
Combined treatment of rats with intrathymic donor alloantigen and a single administration of anti-CD4, but not anti-CD8, MoAb significantly prolongs cardiac allograft survival across a fully major histocompatibility complex mismatched strain combination.
我们之前曾报道，在胸腺内注射同种异体抗原的同时给予抗淋巴细胞血清治疗以清除外周T细胞后，可诱导对心脏同种异体移植物的供体特异性耐受。本研究旨在确定单次给予抗CD4单克隆抗体（MoAb）联合胸腺内注射同种异体抗原后，是否能延长完全主要组织相容性复合体不匹配的心脏同种异体移植物的存活时间。
将雄性布法罗大鼠通过胸腺内或静脉途径给予Lewis脾细胞，同时单次给予抗CD4单克隆抗体（OX-38）或抗CD8 MoAb（OX-8）或两者。在胸腺内同种异体抗原或MoAb预处理或两者预处理21天后进行异位心脏移植。荧光激活细胞分选分析确定淋巴细胞亚群T细胞亚群的变化，体外研究检测受体细胞反应性。
抗CD4 MoAb治疗后21天，早期非特异性免疫抑制已消退，外周CD4+ T细胞恢复80%，受体免疫能力恢复，能够正常排斥心脏同种异体移植物。胸腺内而非静脉内给予同种异体抗原联合抗CD4 MoAb的联合治疗可诱导对后续大鼠心脏同种异体移植物的供体特异性耐受。然而，抗CD8 MoAb联合胸腺内同种异体抗原尽管使CD8+ T细胞亚群显著减少，但未能诱导耐受。
大鼠接受胸腺内供体同种异体抗原和单次给予抗CD4而非抗CD8 MoAb的联合治疗可显著延长完全主要组织相容性复合体不匹配品系组合的心脏同种异体移植物存活时间。
