Eto M, Mayumi H, Nishimura Y, Maeda T, Yoshikai Y, Nomoto K
Department of Immunology, Kyushu University, Fukuoka, Japan.
J Immunol. 1991 Oct 15;147(8):2439-46.
The mechanisms of cyclophosphamide (CP)-induced tolerance were investigated by comparing with those of neonatally induced tolerance. When C3H/He Slc (C3H; H-2k, Mls-1b) mice were given i.v. either AKR/J Sea (AKR; H-2k, Mls-1a) or (AKR x C3H)F1 (AKC3F1; H-2k, Mls-1a/b) spleen cells and treated i.p. with CP 2 days later, a long-lasting skin allograft tolerance to AKR was induced in each case without any signs of graft-vs-host disease (GVHD). However, typical signs of GVHD were observed in the C3H mice neonatally tolerized with AKR spleen cells, but not in those tolerized with AKC3F1 spleen cells. The expression of TCR V beta 6, which is strongly correlated with the reactivity to Mls-1a Ag (of donor AKR origin), in the periphery was quite different between the two types of tolerant C3H mice. Namely, in the lymph nodes of the C3H mice tolerized with AKR spleen cells and CP, only CD4(+)-V beta 6+, but not CD8(+)-V beta 6+, T cells selectively disappeared, whereas both of them were abrogated in the lymph nodes of the C3H mice neonatally tolerized of AKR. By contrast, in the thymus of the two types of tolerant C3H mice, both CD4+CD8- and CD4-CD8+ single-positive thymocytes expressing TCR V beta 6 were clonally deleted, suggesting that the thymic involvement was the same in each type of tolerance. These results suggest that the preferential disappearance of the CD4(+)-V beta 6+ T cells (of host origin) and the effector T cells of GVHD (of donor origin) occurred only in the periphery of the C3H mice tolerized with AKR spleen cells plus CP and was attributable to the destruction of Ag-stimulated T cells by the CP treatment. In contrast, the intrathymic clonal deletion of immature V beta 6+ T cells was a common mechanism for both of the tolerance induction systems.
通过与新生诱导耐受的机制进行比较，研究了环磷酰胺（CP）诱导耐受的机制。当给C3H/He Slc（C3H；H-2k，Mls-1b）小鼠静脉注射AKR/J Sea（AKR；H-2k，Mls-1a）或（AKR×C3H）F1（AKC3F1；H-2k，Mls-1a/b）脾细胞，并在2天后腹腔注射CP时，在每种情况下均诱导出对AKR的持久皮肤同种异体移植耐受，且无任何移植物抗宿主病（GVHD）迹象。然而，在新生期用AKR脾细胞诱导耐受的C3H小鼠中观察到了典型的GVHD体征，但在用AKC3F1脾细胞诱导耐受的小鼠中未观察到。在两种耐受的C3H小鼠外周，与对Mls-1a抗原（供体AKR来源）的反应性密切相关的TCR Vβ6的表达存在很大差异。具体而言，在用AKR脾细胞和CP诱导耐受的C3H小鼠的淋巴结中，仅CD4(+)-Vβ6+ T细胞选择性消失，而CD8(+)-Vβ6+ T细胞未消失，而在新生期用AKR诱导耐受的C3H小鼠的淋巴结中，这两种细胞均消失。相比之下，在两种耐受的C3H小鼠的胸腺中，表达TCR Vβ6的CD4+CD8-和CD4-CD8+单阳性胸腺细胞均发生克隆性缺失，这表明每种耐受类型中胸腺的参与情况相同。这些结果表明，CD4(+)-Vβ6+ T细胞（宿主来源）和GVHD效应T细胞（供体来源）的优先消失仅发生在用AKR脾细胞加CP诱导耐受的C3H小鼠外周，这归因于CP处理对Ag刺激的T细胞的破坏。相比之下，未成熟Vβ6+ T细胞的胸腺内克隆性缺失是两种耐受诱导系统的共同机制。
