Rolink A G, Pals S T, Gleichmann E
J Exp Med. 1983 Feb 1;157(2):755-71. doi: 10.1084/jem.157.2.755.
By induction of a graft-vs.-host reaction (GVHR) in nonirradiated H-2-different F1 mice, one can induce stimulatory pathological symptoms, such as lymphadenopathy and hypergammaglobulinemia, combined with the production of autoantibodies characteristic of systemic lupus erythematosus (SLE). Alternatively, the GVHR can lead to the suppressive pathological symptoms, such as pancytopenia and hypogammaglobulinemia, characteristic of acute GVH disease (GVHD). Whether stimulatory or suppressive symptoms are induced by a GVHR depends, in our view (2-4), on the functional subset of donor T cells activated in the F1 host. The purpose of the present study was to investigate whether class I and/or class II H-2 alloantigens can selectively trigger, out of a pool of unselected donor T cells, those subpopulations of T cells responsible for the stimulatory and suppressive GVH symptoms, respectively. For the induction of the GVHR, 10(8) lymphoid cells from C57BL/6 (B6) donors were injected into three kinds of F1 hybrid mice, which had been bred from H-2 mutant strains on a B6 background. Whereas the I-A-disparate (B6 X bm12)F1 recipients exclusively developed stimulatory GVH symptoms, including SLE-like autoantibodies and immune complex glomerulonephritis, the K locus-disparate (B6 X bm1)F1 recipients showed neither clearly stimulatory nor clearly suppressive GVH symptoms. In marked contrast, the (bm1 X bm12)F1 recipients, which differ from the B6 donor strain by mutations at both K and I-A locus, initially developed stimulatory GVH symptoms, but rapidly thereafter showed the suppressive pathological symptoms of acute GVHD and died. Moreover, spleen cells obtained from (B6 X bm12)F1 mice injected with B6 donor cells helped the primary anti-sheep erythrocyte (SRBC) response of normal (B6 X bm12)F1 spleen cells in vitro, whereas spleen cells (bm1 X bm12)F1 mice injected with B6 donor cells strongly suppressed the primary anti-SRBC response of normal (bm1 X bm12)F1 spleen cells. Spleen cells from the K locus-disparate (B6 X bm1)F1 recipients also suppressed the primary anti-SRBC of normal (B6 X bm1)F1 spleen cells; this suppression, however, was weak when compared with the suppression induced by spleen cells from GVH (bm1 X bm12)F1 mice. Taken together, these findings indicate that a small class II (I-A) antigenic difference suffices to trigger the alloreactive donor T helper cells causing SLE-like GVHD. In contrast, both class I (H-2K) and class II (I-A) differences are required to trigger the subsets of donor T cells responsible for acute GVHD. It appears that alloreactive donor T helper cells induce the alloreactive T suppressor cells, which then act as the suppressor effector cells causing the pancytopenia of acute GVHD. These findings may help to understand the variability of GVH-like diseases caused by a given etiologic agent, their cellular pathogenesis, and association with certain HLA loci.
通过在未受照射的H-2不同的F1小鼠中诱导移植物抗宿主反应（GVHR），可以诱发刺激性病理症状，如淋巴结病和高球蛋白血症，并伴有系统性红斑狼疮（SLE）特有的自身抗体产生。或者，GVHR可导致抑制性病理症状，如全血细胞减少和低球蛋白血症，这是急性移植物抗宿主病（GVHD）的特征。我们认为（2-4），GVHR诱发的是刺激性还是抑制性症状，取决于在F1宿主中被激活的供体T细胞的功能亚群。本研究的目的是调查I类和/或II类H-2同种异体抗原是否能从未经选择的供体T细胞库中分别选择性地触发负责刺激性和抑制性GVH症状的T细胞亚群。为了诱导GVHR，将来自C57BL/6（B6）供体的10⁸个淋巴细胞注射到三种F1杂交小鼠体内，这些小鼠是在B6背景上由H-2突变株培育而成的。I-A不同的（B6×bm12）F1受体只出现刺激性GVH症状，包括SLE样自身抗体和免疫复合物性肾小球肾炎，而K位点不同的（B6×bm1）F1受体既没有明显的刺激性GVH症状，也没有明显的抑制性GVH症状。与之形成鲜明对比的是，（bm1×bm12）F1受体与B6供体菌株在K和I-A位点均有突变，最初出现刺激性GVH症状，但随后迅速出现急性GVHD的抑制性病理症状并死亡。此外，注射了B6供体细胞的（B6×bm12）F1小鼠的脾细胞在体外促进了正常（B6×bm12）F1脾细胞对绵羊红细胞（SRBC）的初次反应，而注射了B6供体细胞的（bm1×bm12）F1小鼠的脾细胞则强烈抑制了正常（bm1×bm12）F1脾细胞对SRBC的初次反应。K位点不同的（B6×bm1）F1受体的脾细胞也抑制了正常（B6×bm1）F1脾细胞对SRBC的初次反应；然而，与GVH（bm1×bm12）F1小鼠的脾细胞诱导的抑制作用相比，这种抑制作用较弱。综上所述，这些发现表明，II类（I-A）的微小抗原差异足以触发引起SLE样GVHD的同种异体反应性供体T辅助细胞。相比之下，I类（H-2K）和II类（I-A）差异都需要触发负责急性GVHD的供体T细胞亚群。看来同种异体反应性供体T辅助细胞诱导了同种异体反应性T抑制细胞，然后这些细胞作为抑制效应细胞导致急性GVHD的全血细胞减少。这些发现可能有助于理解由特定病原体引起的GVH样疾病的变异性、它们的细胞发病机制以及与某些HLA位点相关性。
