Prevention Type 1 diabetes by soluble, MHC II-peptide

该提案的总体目标是通过使用多价MHC II类/高价肽嵌合体来预防自身免疫性糖尿病的发展。还将研究通过多价MHC II/肽嵌合体操纵免疫系统的机制和后果。具体目标是：（1）确定可溶性多价MHC II/肽嵌合体与二价MHC II/肽嵌合体相比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中长期保护的细胞机制，和（3）研究通过这些嵌合分子保护小鼠免于糖尿病的TR细胞信号传导事件。该研究将在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产生由HLA-DR*0401等位基因和人类中最常见的致糖尿病肽GAD和胰岛素原衍生肽组成的人DEF样分子（hu-DEF）。在用GAD 65肽免疫或不免疫后，在Tg小鼠（鼠MHcalphabeta II类-/-，人HLA-DR* 0301和-DR*0401 +/+）中评价hu-CEF的治疗功效，然后用来自HLA-DR匹配的IDDM患者或来自其高危亲属的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.