Prevention Type 1 diabetes by soluble, MHC II-peptide

这项建议的总体目标是通过使用高价的多价MHC II类/多肽嵌合体来预防自身免疫性糖尿病的发展。多价MHC II/多肽嵌合体操纵免疫系统的机制和后果也将被研究。其具体目的是：(1)与二价MHC II/肽嵌合体相比，确定可溶的多价MHC II/肽嵌合体在自身免疫性糖尿病中的保护能力；(2)研究用这些嵌合分子治疗的小鼠的长期保护的细胞机制；(3)研究这些嵌合分子对糖尿病小鼠保护的tr细胞信号事件。这项拟议的研究将在I型糖尿病的双转基因小鼠模型中进行。令人满意的结果将导致人类DEF样分子(HU-DEF)的产生，该分子由HLA-DR*0401等位基因和人类最常见的致糖尿病多肽GAD和胰岛素原衍生多肽组成。HU-CEF的治疗效果将在GAD65肽免疫或不免疫后在TG小鼠(小鼠MHcalphabetaII-/-，人HLA-DR*0301和-DR*0401/)上进行评估，然后与来自HLA-DR相合的IDDM患者或其高危亲属的T细胞过继转移。

The overall goal of this proposal is to prevent the development of autoimmune diabetes by using multivalent MHC class II/peptide chimeras of high valency. The mechanisms and consequences of manipulating the immune system by multivalent MHC II/peptide chimeras will also be investigated. The specific aims are: (1) to determine the protective capacity of soluble, multivalent MHC II/peptide chimeras in autoimmune diabetes as compared to bivalent MHC II/peptide chimera, (2) to study the cellular mechanisms of long-term protection in mice treated with these chimeric molecules , and (3) to study the TR-cell signaling events in mice protected against diabetes by these chimeric molecules. The proposed study will be carried out in a double transgenic mouse model for Type I Diabetes. Satisfactory results will lead to the generation of a human DEF-like molecule (hu- DEF) consisting of the HLA-DR*0401 allele, and the most common diabetogenic peptide in humans, GAD-, and pro-insulin- derived peptides. The therapeutic efficacy of hu-CEF will be evaluated in Tg mice (murine MHcalphabeta class II-/-, human HLA-DR* 0301 and -DR*0401 +/+) after immunization or not with GAD65 peptide, and then adoptively transferred with T-cells from HLA-DR-matched patients with IDDM, or from their at-high risk relatives.