INHIBITION OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS BY INHALATION BUT NOT ORAL-ADMINISTRATION OF THE ENCEPHALITOGENIC PEPTIDE - INFLUENCE OF MHC BINDING-AFFINITY
INHIBITION OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS BY INHALATION BUT NOT ORAL-ADMINISTRATION OF THE ENCEPHALITOGENIC PEPTIDE - INFLUENCE OF MHC BINDING-AFFINITY
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DOI：
10.1093/intimm/5.9.1159
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发表时间：
1993-09-01
影响因子：
4.4
通讯作者：
WRAITH, DC
中科院分区：
文献类型：
--
作者：
METZLER, B;WRAITH, DC
本研究探讨了通过粘膜表面的抗原管理作为一种潜在的手段诱导抗原特异性无反应性的实验性自身免疫性脑脊髓炎（EAE）。在EAE的H-2u小鼠模型中，髓鞘碱性蛋白的乙酰化N-末端肽代表了一种占优势的T细胞表位，其本身足以诱导疾病。在广泛的剂量范围内口服致脑炎肽未能诱导口服耐受EAE。与此形成鲜明对比的是，当在疾病诱导前给药时，单次鼻内给药该肽（Ac 1 - 9或Ac 1 - 11）可显著抑制EAE。我们进一步研究了这种现象，通过使用两个类似物的Ac 1 - 11与丙氨酸或酪氨酸的位置4，显示出更高的亲和力结合的I-Au分子比原来的肽与赖氨酸在这个位置。保护EAE的程度与单个肽对II类MHC的亲和力之间呈正相关。肽吸入不仅抑制由皮下注射致脑炎肽诱导的EAE，而且抑制由潜在自身抗原的复杂混合物如脊髓匀浆诱导的疾病。因此，与口服耐受相反，在没有额外的调节表位的情况下，通过吸入肽的无反应性是可诱导的致脑炎肽。然而，发现一个单一的表位可以防止EAE诱导的全脊髓匀浆意味着，影响其他潜在的自我表位的调节机制可能发挥重要作用。
This study explores antigen administration via mucosal surfaces as a potential means of inducing antigen-specific non-responsiveness in experimental autoimmune encephalomyelitis (EAE). In the H-2u mouse model of EAE, the acetylated N-terminal peptide of myelin basic protein represents a dominant T cell epitope which on its own is sufficient to induce disease. Oral administration of the encephalitogenic peptide over a wide range of doses failed to induce oral tolerance to EAE. In marked contrast, a single intranasal dose of this peptide (Ac1 - 9 or Ac1 - 11) profoundly inhibited EAE when administered prior to disease induction. We investigated this phenomen further by using two analogues of Ac1 - 11 with alanine or tyrosine at position 4 which display higher affinity binding to the I-Au molecule than the original peptide with lysine at this position. There was a positive correlation between the degree of protection from EAE and the affinity of individual peptides for class II MHC. Peptide inhalation inhibited not only EAE induced by subcutaneous injection of the encephalitogenic peptide but also disease induced by a complex mixture of potential auto-antigens such as spinal cord homogenate. Thus, in contrast to oral tolerance, nonresponsiveness by peptide inhalation is inducible with the encephalitogenic peptide in the absence of additional regulatory epitopes. The finding that a single epitope may protect against EAE induced with whole spinal cord homogenate implies, however, that regulatory mechanisms affecting additional potential self-epitopes may play a significant role.