Tolerance induction in EAE by epicutaneous immunization

描述（由申请人提供）：人类疾病多发性硬化症（MS）是一种由T辅助细胞-1 （Th1）介导的炎症性和脱髓鞘性神经系统疾病。实验性过敏性脑脊髓炎（EAE）是研究ms最完善的动物模型，在某些近交小鼠品系中，用髓鞘蛋白自身抗原如髓鞘碱性蛋白（MBP）、蛋白脂质蛋白（PLP）或髓鞘少突胶质细胞蛋白（MOG）佐剂免疫后，可积极诱导EAE。最近，我们发现，在用MBP特异性T细胞受体免疫转基因小鼠之前，通过表皮（皮肤）途径将MBP肽在贴片中免疫它们以诱导疾病，这些小鼠可以免受EAE。这种保护是抗原特异性的，抗原剂量依赖性的，由CD4 T细胞介导，将保护转移到初始受体。此外，髓磷脂来源的自体肽皮外免疫以抗原特异性和抗原剂量依赖性的方式保护正常小鼠不发生EAE，包括在疾病的复发-缓解模型中。然而，当这些小鼠在佐剂中外源性免疫它们的同源肽时，疾病加速。这一建议描述了三个具体的目的，将试图阐明机制，通过表皮给药的自肽诱导小鼠显性耐受。一些目的集中在确定皮肤树突状细胞在转基因和非转基因小鼠模型中诱导耐受性的作用。拟议的研究还将探讨在正常小鼠中诱导和操作耐受性的机制。在正常小鼠中，我们将探索Th2细胞因子是否参与介导疾病保护：特别是在（SJLxPL/J） f1小鼠模型中。最后，我们将进行实验来检验自体抗原肽皮外免疫是否能够改善EAE。

DESCRIPTION (provided by applicant): The human disease multiple sclerosis (MS) is an inflammatory and demyelinating neurological disease that is mediated by T helper-1 (Th1) cells. Experimental allergic encephalomyelitis (EAE) is the most well-established animal model for the study of MS. EAE can be actively induced in certain inbred mouse strains following immunization with myelin protein autoantigens such as myelin basic protein (MBP), proteolipid protein (PLP) or myelin oligodendrocyte protein (MOG) in adjuvant. Recently, we found that when we immunize transgenic mice carrying a MBP specific T cell receptor via the epicutaneous (skin) route with MBP peptides in a patch prior to immunizing them with the same peptide to induce disease, such mice were protected from EAE. This protection was antigen-specific, antigen dose-dependent and was mediated by CD4 T cells that transferred protection to naive recipients. In addition, epicutaneous immunization with myelin-derived self-peptides protected normal mice from developing EAE in an antigen-specific and antigen dose-dependent manner including in a relapsing-remitting model of the disease. However, when these same mice are epicutaneously immunized with their cognate peptide in adjuvant, disease was accelerated. This proposal describes three specific aims that will attempt to elucidate the mechanism(s) by which the epicutaneous administration of self-peptide induces dominant tolerance in mice. Some aims focus on determining the role of skin dendritic cells in the induction of tolerance in both the transgenic and non-transgenic mouse models. Proposed studies will also investigate the mechanism(s) by which tolerance is induced and operates in normal mice. In normal mice, we will explore whether Th2 cytokines are involved in mediating protection from disease: specifically in the (SJLxPL/J)F 1 mouse model. Finally, we will carry out experiments to test whether epicutaneous immunization with autoantigenic peptides is capable of ameliorating EAE.