Hammond K J, Poulton L D, Palmisano L J, Silveira P A, Godfrey D I, Baxter A G
Autoimmunity Research Group, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia.
J Exp Med. 1998 Apr 6;187(7):1047-56. doi: 10.1084/jem.187.7.1047.
We have previously shown that nonobese diabetic (NOD) mice are selectively deficient in alpha/beta-T cell receptor (TCR)+CD4-CD8- NKT cells, a defect that may contribute to their susceptibility to the spontaneous development of insulin-dependent diabetes mellitus (IDDM). The role of NKT cells in protection from IDDM in NOD mice was studied by the infusion of thymocyte subsets into young female NOD mice. A single intravenous injection of 10(6) CD4-/lowCD8- or CD4-CD8- thymocytes from female (BALB/c x NOD)F1 donors protected intact NOD mice from the spontaneous onset of clinical IDDM. Insulitis was still present in some recipient mice, although the cell infiltrates were principally periductal and periislet, rather than the intraislet pattern characteristic of insulitis in unmanipulated NOD mice. Protection was not associated with the induction of "allogenic tolerance" or systemic autoimmunity. Accelerated IDDM occurs after injection of splenocytes from NOD donors into irradiated adult NOD recipients. When alpha/beta-TCR+ and alpha/beta-TCR- subsets of CD4-CD8- thymocytes were transferred with diabetogenic splenocytes and compared for their ability to prevent the development of IDDM in irradiated adult recipients, only the alpha/beta-TCR+ population was protective, confirming that NKT cells were responsible for this activity. The protective effect in the induced model of IDDM was neutralized by anti-IL-4 and anti-IL-10 monoclonal antibodies in vivo, indicating a role for at least one of these cytokines in NKT cell-mediated protection. These results have significant implications for the pathogenesis and potential prevention of IDDM in humans.
我们先前已表明，非肥胖糖尿病（NOD）小鼠在α/β - T细胞受体（TCR）+ CD4 - CD8 - NKT细胞方面存在选择性缺陷，这一缺陷可能导致它们易患胰岛素依赖型糖尿病（IDDM）的自发发展。通过将胸腺细胞亚群注入年轻雌性NOD小鼠，研究了NKT细胞在NOD小鼠预防IDDM中的作用。单次静脉注射来自雌性（BALB/c×NOD）F1供体的10^6个CD4 - /低CD8 - 或CD4 - CD8 - 胸腺细胞，可保护未处理的NOD小鼠免受临床IDDM的自发发作。尽管在一些受体小鼠中仍存在胰岛炎，但其细胞浸润主要是导管周围和胰岛周围的，而非未处理的NOD小鼠胰岛炎特征性的胰岛内模式。这种保护作用与“同种异体耐受”或全身性自身免疫的诱导无关。将NOD供体的脾细胞注入经照射的成年NOD受体后，IDDM会加速发生。当将CD4 - CD8 - 胸腺细胞的α/β - TCR + 和α/β - TCR - 亚群与致糖尿病脾细胞一起转移，并比较它们在经照射的成年受体中预防IDDM发展的能力时，只有α/β - TCR + 群体具有保护作用，这证实了NKT细胞负责这种活性。在体内，抗IL - 4和抗IL - 10单克隆抗体可中和IDDM诱导模型中的保护作用，表明这些细胞因子中的至少一种在NKT细胞介导的保护中发挥作用。这些结果对人类IDDM的发病机制和潜在预防具有重要意义。
