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）是一种由辅助性T细胞-1（Th 1）介导的炎性和脱髓鞘性神经系统疾病。 实验性变态反应性脑脊髓炎（Experimental allergic encephalomyelitis，EAE）是研究多发性硬化症最成熟的动物模型。 最近，我们发现，当我们免疫转基因小鼠携带MBP特异性T细胞受体，通过表皮（皮肤）途径与MBP肽在补丁之前，用相同的肽免疫它们诱导疾病，这样的小鼠被保护免受EAE。 这种保护是抗原特异性的，抗原剂量依赖性的，并通过CD 4 T细胞介导，将保护转移到幼稚受体。 此外，髓鞘衍生的自身肽的表皮免疫保护正常小鼠以抗原特异性和抗原剂量依赖性的方式免于发展EAE，包括在疾病的复发-缓解模型中。 然而，当这些相同的小鼠用其在佐剂中的同源肽进行表皮免疫时，疾病加速。 该提案描述了三个具体目的，其将试图阐明表皮施用自身肽诱导小鼠显性耐受的机制。一些目标集中于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。 拟定的研究还将研究诱导耐受性并在正常小鼠中发挥作用的机制。 在正常小鼠中，我们将探索是否Th 2细胞因子参与介导疾病保护：特别是在（SJLxPL/J）F1小鼠模型中。 最后，我们将进行实验来测试用自身抗原肽进行表皮免疫是否能够改善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.