Anderton S M, Burkhart C, Liu G Y, Metzler B, Wraith D C
Department of Pathology and Microbiology, University of Bristol, School of Medical Sciences, UK.
Novartis Found Symp. 1998;215:120-31; discussion 131-6, 186-90. doi: 10.1002/9780470515525.ch9.
Antigen-specific tolerance induction is the ultimate goal for specific immunotherapy of autoimmune diseases. Here we will discuss recent experiments designed to induce tolerance following mucosal administration of antigens in a mouse model of experimental autoimmune encephalomyelitis (EAE). We were unable to induce oral tolerance either with whole myelin, myelin basic protein (MBP) or the immunodominant peptide antigen. Oral tolerance was possible, however, with an analogue of the immunodominant peptide modified to increase its affinity for the restricting major histocompatibility complex (MHC) antigen. By contrast, intranasal deposition of peptide antigen proved highly effective for both prevention and treatment of EAE. Prevention of disease was directly related to the antigenic property of the peptide which, in itself, was related to affinity for MHC. Notably, administration of a single peptide was shown to inhibit disease involving multiple epitopes. We investigated the resulting bystander regulation by studying the cellular basis of peripheral tolerance in a transgenic model. These studies indicate that bystander regulation may be the consequence of selective cytokine secretion.
抗原特异性耐受诱导是自身免疫性疾病特异性免疫治疗的最终目标。在此，我们将讨论最近在实验性自身免疫性脑脊髓炎（EAE）小鼠模型中，旨在通过黏膜给予抗原后诱导耐受的实验。我们无法用全髓磷脂、髓磷脂碱性蛋白（MBP）或免疫显性肽抗原来诱导口服耐受。然而，用一种经修饰以增加其对限制性主要组织相容性复合体（MHC）抗原亲和力的免疫显性肽类似物则可以诱导口服耐受。相比之下，肽抗原的鼻内沉积被证明对EAE的预防和治疗都非常有效。疾病的预防与肽的抗原特性直接相关，而肽的抗原特性本身又与对MHC的亲和力有关。值得注意的是，给予单一肽被证明可以抑制涉及多个表位的疾病。我们通过在转基因模型中研究外周耐受的细胞基础来探究由此产生的旁观者调节作用。这些研究表明，旁观者调节可能是选择性细胞因子分泌的结果。
