Chai Jian-Guo, James Edward, Dewchand Hamlata, Simpson Elizabeth, Scott Diane
Transplantation Biology Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom.
Blood. 2004 May 15;103(10):3951-9. doi: 10.1182/blood-2003-11-3763. Epub 2004 Jan 15.
Induction of antigen-specific tolerance to transplantation antigens is desirable to control host-versus-graft and graft-versus-host reactions. Following molecular identification of a set of minor histocompatibility (H) antigens, we have used selected HY peptide epitopes for this purpose. Intranasal administration of individual major histocompatibility complex (MHC) class II-restricted HY peptides induces indefinite survival of syngeneic male skin grafts and allows engraftment of male bone marrow. Tolerance involves linked suppression to additional HY epitopes on test grafts. Long-term tolerance also requires suppression of emerging thymic emigrants. It does not involve deletion. HY peptide-specific CD4(+) and CD8(+) T cells expand on re-exposure to male antigen; these expansions are smaller in tolerant than control mice and fewer HY-specific cells from tolerant females secrete interferon gamma and interleukin 10 (IL-10). Significantly, CD4(+) cells from peptide-pretreated females fail to make IL-2 responses to cognate peptide, limiting expansion of the HY-specific CD8(+) populations that can cause graft rejection. Consistent with this, tolerance induction by HY peptide is abrogated by coadministration of lipopolysaccharide. IL-10 does not appear to be critically involved because tolerance is inducible in IL-10-deficient mice. Adoptive transfer of tolerance into naive neonatal recipients by splenocytes from long-term tolerant donors provides evidence for involvement of regulatory cells.
诱导对移植抗原的抗原特异性耐受对于控制宿主抗移植物反应和移植物抗宿主反应是很有必要的。在对一组次要组织相容性（H）抗原进行分子鉴定之后，我们已为此目的使用了选定的HY肽表位。经鼻给予单个主要组织相容性复合体（MHC）II类限制性HY肽可诱导同基因雄性皮肤移植物无限期存活，并允许雄性骨髓植入。耐受涉及对测试移植物上其他HY表位的连锁抑制。长期耐受还需要抑制新出现的胸腺迁出细胞。它不涉及缺失。再次接触雄性抗原时，HY肽特异性CD4(+)和CD8(+) T细胞会扩增；与对照小鼠相比，耐受性小鼠中的这些扩增较小，并且来自耐受性雌性的HY特异性细胞分泌干扰素γ和白细胞介素10（IL-10）的较少。值得注意的是，来自经肽预处理的雌性的CD4(+)细胞对同源肽不产生IL-2反应，从而限制了可导致移植物排斥的HY特异性CD8(+)群体的扩增。与此一致的是，同时给予脂多糖可消除HY肽诱导的耐受。IL-10似乎并非关键因素，因为在IL-10缺陷小鼠中也可诱导耐受。长期耐受供体的脾细胞将耐受性过继转移至新生幼稚受体，这为调节性细胞的参与提供了证据。
