Active tolerance induction and involvement of CD1d‐restricted NKT cells in anti‐CD3 F(ab¡¯)2 treatment reversed new onset diabetes in NOD mice
Active tolerance induction and involvement of CD1d‐restricted NKT cells in anti‐CD3 F(ab¡¯)2 treatment reversed new onset diabetes in NOD mice
复制标题
DOI：
10.1096/fasebj.22.2_supplement.458
复制
发表时间：
2008-04
期刊：
影响因子：
--
通讯作者：
G. Han;Guojiang Chen;Yan Li;B. Shen
中科院分区：
文献类型：
--
作者：
G. Han;Guojiang Chen;Yan Li;B. Shen
抗 CD3 F(ab’)2 单克隆抗体的应用最近已扩大到治疗包括 1 型糖尿病在内的已知自身免疫性疾病。然而，其基本机制仍不清楚。在这里，我们报告，短阶段施用抗 CD3 F(ab')2 抗体有效地将新发糖尿病非肥胖糖尿病小鼠转化为正常血糖，并重建胰腺 β 细胞特异性耐受，这种治疗效果持续超过 40 周。对参与机制的理解揭示了免疫调节 CD1d 限制性自然杀伤 T (NKT) 细胞群的产生，其特点是 Th2 反应增强并分泌更多 IL-10。 IL-4 和/或 IL-10 生物活性的体内中和消除了这种抗 CD3 介导的作用。重要的是，当将缓解小鼠衍生的 NKT 细胞与致糖尿病细胞共转移到 NOD 严重联合免疫缺陷 (NOD.scid) 小鼠中时，这些 NKT 细胞足以延缓或预防糖尿病的发作。这些数据表明，CD1d 限制性 NKT 细胞可能在抗 CD3 抗体诱导的糖尿病缓解和免疫耐受恢复中发挥关键作用。
The application of anti‐CD3 F(ab’)2 monoclonal antibodies recently has been expanded to treat established autoimmune diseases including type 1 diabetes. However, the underling mechanisms remain largely unclear. Here, we report that short‐phase administration of anti‐CD3 F(ab’)2 antibodies efficiently converted new‐onset diabetic nonobese diabetic mice into normoglycemia and re‐established pancreatic β‐cell specific tolerance, this therapeutic effect lasting over 40 weeks. The understanding of involving mechanism revealed the generation of a population of immunoregulatory CD1d‐restricted natural killer T (NKT) cells, which was marked by enhanced Th2 response and secreting more IL‐10. In vivo neutralization of IL‐4 and/or IL‐10 bioactivity abrogated this anti‐CD3‐mediated effect. Importantly, when cotransfer of remitting mice derived NKT cells into NOD‐severe combined immunodeficient (NOD.scid) mice with diabetogenic cells, these NKT cells were sufficient to delay or prevent the onset of diabetes. These data suggested that CD1d‐restricted NKT cells might play a critical role in anti‐CD3 antibody induced diabetes remission and immune tolerance restoration.