Davies J D, Leong L Y, Mellor A, Cobbold S P, Waldmann H
Department of Biology and Cancer Center, University of California San Diego, La Jolla, 92093-0063, USA.
J Immunol. 1996 May 15;156(10):3602-7.
Allogeneic tissues transplanted to mice treated with CD4- and CD8-specific Abs are often accepted indefinitely due to the induction of immunologic tolerance. When transplantation tolerance was induced to grafts mismatched at multiple minor histocompatibility loci, Ag specificity was inferred because third party grafts, mismatched at the MHC, were rejected normally. However, some "third party" grafts were either accepted, or rejected more slowly. Tolerant mice possess CD4+ cells, which suppress rejection by T cells reacting to the same grafts. Therefore, we hypothesized that tolerated third party grafts might share Ags with the original tolerizing graft, and that these Ags are a target for such suppression. To test this idea, we tolerized mice to a set of minor Ags (B10 minors) and challenged them with third party grafts that carried those minors, as well as an additional strong transplantation Ag, the class I MHC molecule, H-2Kb. This class I molecule acts as a good target for rejection in both naive mice and in mice tolerized to B10 minors. However, when this third party class I molecule is provided "linked" to those B10 minors on an F1 graft, rejection was significantly impaired. The data suggest that suppression within tolerant animals operates locally (perhaps on the same APC) via linked recognition. In addition, our preliminary findings suggest that suppression via linked recognition can also lead to tolerance to the third party Ag.
移植到用CD4和CD8特异性抗体处理过的小鼠体内的同种异体组织，由于免疫耐受的诱导，通常会被无限期接受。当对在多个次要组织相容性位点不匹配的移植物诱导移植耐受时，由于MHC不匹配的第三方移植物被正常排斥，所以推断出抗原特异性。然而，一些“第三方”移植物要么被接受，要么排斥得更慢。耐受小鼠拥有CD4+细胞，这些细胞可抑制对相同移植物产生反应的T细胞的排斥作用。因此，我们推测被耐受的第三方移植物可能与原始的耐受诱导移植物共享抗原，并且这些抗原是这种抑制作用的靶点。为了验证这一想法，我们使小鼠对一组次要抗原（B10次要抗原）产生耐受，并用携带这些次要抗原以及另一种强移植抗原即I类MHC分子H-2Kb的第三方移植物对它们进行攻击。这种I类分子在未致敏小鼠和对B10次要抗原产生耐受的小鼠中都是良好的排斥靶点。然而，当这种第三方I类分子在F1移植物上与那些B10次要抗原“连锁”提供时，排斥反应明显受损。数据表明，耐受动物体内的抑制作用通过连锁识别在局部起作用（可能作用于同一个抗原呈递细胞）。此外，我们的初步研究结果表明，通过连锁识别产生的抑制作用也可导致对第三方抗原的耐受。
