Tan L J, Kennedy M K, Miller S D
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611.
J Immunol. 1992 May 1;148(9):2748-55.
Ag-specific tolerance induced by the i.v. administration of splenocytes coupled with mouse spinal cord homogenate, containing a mixture of myelin Ag, dramatically inhibits development and expression of clinical and histologic signs of both active and adoptive forms of relapsing experimental autoimmune encephalomyelitis (R-EAE) in the SJL/J host. Here we examined the dose-dependency, route of tolerogen administration, and fine neuroantigen specificity of inhibition of adoptive R-EAE. Expression of clinical R-EAE induced by a polyclonal population of bovine myelin basic protein (MBP)-specific effector T cells was dramatically inhibited in a dose-dependent manner following the i.v., but not s.c. or i.p., injection of MBP-coupled splenocytes. The exquisite Ag specificity of the inhibition was evident by the observation that splenocytes coupled with intact bovine MBP or species variants of MBP homologous with bovine MBP within the major encephalitogenic region (amino acids 84-104), but not with proteolipid protein or mouse kidney homogenate, were able to suppress disease expression. Splenocytes coupled with the MBP84-104 peptide, containing a nested set of the major SJL/J encephalitogenic epitopes, completely inhibited peptide-specific T cell responses, but only partially inhibited the expression of disease transferred by T cells specific for intact MBP, suggesting the participation of T cell responses specific for additional MBP determinants in disease pathogenesis. However, splenocytes coupled with previously identified minor SJL/J encephalitogenic epitopes (MBP91-104 or MBP17-27), or with the Lewis rat major encephalitogenic epitope (MBP68-86), did not suppress disease expression. Collectively, the results demonstrate that MBP84-104-specific T cells and T cells specific for an as yet unidentified MBP epitope(s) contribute to the pathology of R-EAE. In addition, the results demonstrate that peptide-specific tolerance induction appears to have potential for the treatment of T cell-mediated inflammatory diseases.
静脉注射与含有髓磷脂抗原混合物的小鼠脊髓匀浆偶联的脾细胞所诱导的抗原特异性耐受，可显著抑制SJL/J宿主中复发型实验性自身免疫性脑脊髓炎（R-EAE）的主动和过继形式的临床及组织学症状的发展和表达。在此，我们研究了过继性R-EAE抑制的剂量依赖性、耐受原给药途径以及精细神经抗原特异性。在静脉注射（而非皮下或腹腔注射）MBP偶联的脾细胞后，由多克隆牛髓磷脂碱性蛋白（MBP）特异性效应T细胞诱导的临床R-EAE的表达以剂量依赖性方式受到显著抑制。通过观察发现，与完整的牛MBP或在主要致脑炎区域（氨基酸84 - 104）与牛MBP同源的MBP物种变体偶联的脾细胞能够抑制疾病表达，而与蛋白脂蛋白或小鼠肾匀浆偶联的脾细胞则不能，这表明了抑制作用具有高度的抗原特异性。与包含主要SJL/J致脑炎表位嵌套集的MBP84 - 104肽偶联的脾细胞完全抑制了肽特异性T细胞反应，但仅部分抑制了由完整MBP特异性T细胞转移的疾病表达，这表明针对其他MBP决定簇的T细胞反应参与了疾病发病机制。然而，与先前确定的次要SJL/J致脑炎表位（MBP91 - 104或MBP17 - 27）或与Lewis大鼠主要致脑炎表位（MBP68 - 86）偶联的脾细胞并未抑制疾病表达。总体而言，结果表明MBP84 - 104特异性T细胞以及针对尚未确定的MBP表位的特异性T细胞促成了R-EAE的病理过程。此外，结果表明肽特异性耐受诱导似乎具有治疗T细胞介导的炎性疾病的潜力。
