Development of new therapy for type 1 diabetes targeting for IRF-4 (interferon regulatory factor-4)

为了研究IRF 4靶向治疗在1型糖尿病中的有效性，我们产生IRF 4缺陷型NOD小鼠并研究表型。我们发现自身免疫性糖尿病/胰岛炎/自身胰岛素抗体的进展在IRF 4-/- NOD小鼠中被完全抑制，在杂合子（IRF 4 +/-NOD）小鼠中也被显著抑制。结合CD 4+和CD 8 +T细胞亚群的适应性转移研究表明，IRF 4对CD 4+和CD 8 + T细胞的效应功能都是必需的。IRF 4表达减少与记忆T细胞和产生IL-17的CD 4 +T细胞以及CD 8 +T细胞中产生颗粒酶B的细胞减少有关。我们证明了IRF 4在NOD小鼠自身免疫性糖尿病中对T细胞的效应功能至关重要，IRF 4可能是预防人类1型糖尿病的靶点

To investigate the effectiveness of IRF4 targeting therapy in type 1 diabetes, we generated IRF4 deficient NOD mouse and investigated the phenotypes. We found that progression of autoimmune diabetes / insulitis / autoinsulin antibody were completely suppressed in IRF4-/- NOD mice, also significantly suppressed in heterozygous (IRF4+/-NOD) mice. Adaptive transfer study with combined CD4+and CD8+T cell subsets exhibited that IRF4 is essential for effecter functions in both CD4+ and CD8+ T cells. Less IRF4 expression was associated with reduction of memory T cells and IL-17 producing CD4+T cells, as well as Granzym B producing cells in CD8+T cells. We documented IRF4 is essential for effector function of T cells in autoimmune diabetes in NOD mouse and IRF4 is possible target for prevention for human type 1 diabetes