DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice
DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice
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DOI：
10.1038/sj.gt.3302578
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发表时间：
2005-12-01
期刊：
影响因子：
5.1
通讯作者：
Trucco, M
中科院分区：
文献类型：
--
作者：
Chang, Y;Yap, S;Trucco, M
1型糖尿病（T1 D）是一种T细胞介导的自身免疫性疾病，可归因于非肥胖糖尿病（NOD）小鼠的许多缺陷，包括损害抗原呈递的共刺激分子表达缺陷。因此，这种抗原呈递缺陷可能导致通过自身反应性T细胞的负选择/调节诱导致耐受性应答的能力降低。不适当激活的T细胞似乎能够诱导自身免疫反应，导致糖尿病。为了通过调节共刺激来重建对自身抗原的耐受性，我们构建并测试了一种新型的编码膜结合前胰岛素原（mbPPI）的DNA疫苗和编码突变型B7.1/CD 40 L（mB7.1/CD 40 L）融合蛋白的嵌合基因载体。该突变体B7.1结合CTLA 4但不结合CD 28。我们报道了用mbPPI沿着mB7.1/CD 40 L DNA载体免疫的年轻NOD小鼠显著降低了糖尿病发病率，而用CTLA 4/IgG 1治疗则加重了糖尿病。总之，mbPPI和mB7.1/CD 40 L的组合能够保护NOD小鼠免受自身免疫和糖尿病的影响，这可能是通过促进自身抗原PPI的更有效呈递和通过负调节自身反应性T细胞诱导对PPI的特异性耐受。
Type 1 diabetes (T1D), a T-cell-mediated autoimmune disease, could be attributed to many defects in nonobese diabetic (NOD) mice, including deficient expressions of costimulatory molecules that impair antigen presentation. Thus, this deficient antigen presentation may result in a reduced ability to induce a tolerogenic response through negative selection/regulation of autoreactive T cells. Improperly activated T cells seem to be able to induce autoimmune responses causing diabetes. To re-establish tolerance to autoantigens by modulating costimulation, we constructed and tested a new type of DNA vaccine encoding a membrane-bound preproinsulin (mbPPI) and a chimeric gene vector encoding mutant B7.1/CD40L (mB7.1/CD40L) fusion protein. This mutant B7.1 binds CTLA4 but not CD28. We report that young NOD mice immunized with mbPPI along with mB7.1/CD40L DNA vectors significantly reduced diabetes incidence while treatment with CTLA4/IgG1 exacerbated diabetes. In conclusion, the combination of mbPPI and mB7.1/CD40L was able to protect against autoimmunity and diabetes in NOD mice possibly by promoting a more efficient presentation of autoantigen PPI and inducing specific tolerance to PPI by negatively regulating autoreactive T cells.