Trembleau S, Penna G, Gregori S, Chapman H D, Serreze D V, Magram J, Adorini L
Roche Milano Ricerche, Milano, Italy.
J Immunol. 1999 Sep 1;163(5):2960-8.
IL-12 and IL-12 antagonist administration to nonobese diabetic (NOD) mice accelerates and prevents insulin-dependent diabetes mellitus (IDDM), respectively. To further define the role of endogenous IL-12 in the development of diabetogenic Th1 cells, IL-12-deficient NOD mice were generated and analyzed. Th1 responses to exogenous Ags were reduced by approximately 80% in draining lymph nodes of these mice, and addition of IL-12, but not IL-18, restored Th1 development in vitro, indicating a nonredundant role of IL-12. Moreover, spontaneous Th1 responses to a self Ag, the tyrosine phosphatase-like IA-2, were undetectable in lymphoid organs from IL-12-deficient, in contrast to wild-type, NOD mice. Nevertheless, wild-type and IL-12-deficient NOD mice developed similar insulitis and IDDM. Both in wild-type and IL-12-deficient NOD mice, approximately 20% of pancreas-infiltrating CD4+ T cells produced IFN-gamma, whereas very few produced IL-10 or IL-4, indicating that IDDM was associated with a type 1 T cell infiltrate in the target organ. T cell recruitment in the pancreas seemed favored in IL-12-deficient NOD mice, as revealed by increased P-selectin ligand expression on pancreas-infiltrating T cells, and this could, at least in part, compensate for the defective Th1 cell pool recruitable from peripheral lymphoid organs. Residual Th1 cells could also accumulate in the pancreas of IL-12-deficient NOD mice because Th2 cells were not induced, in contrast to wild-type NOD mice treated with an IL-12 antagonist. Thus, a regulatory pathway seems necessary to counteract the pathogenic Th1 cells that develop in the absence of IL-12 in a spontaneous chronic progressive autoimmune disease under polygenic control, such as IDDM.
给非肥胖糖尿病（NOD）小鼠注射白细胞介素-12（IL-12）和IL-12拮抗剂，分别会加速和预防胰岛素依赖型糖尿病（IDDM）。为了进一步明确内源性IL-12在致糖尿病性Th1细胞发育中的作用，我们构建并分析了IL-12缺陷型NOD小鼠。在这些小鼠的引流淋巴结中，对外源性抗原的Th1反应降低了约80%，添加IL-12而非IL-18可在体外恢复Th1细胞的发育，这表明IL-12具有不可替代的作用。此外，与野生型NOD小鼠相比，在IL-12缺陷型小鼠的淋巴器官中未检测到对自身抗原酪氨酸磷酸酶样IA-2的自发Th1反应。然而，野生型和IL-12缺陷型NOD小鼠都发生了类似的胰岛炎和IDDM。在野生型和IL-12缺陷型NOD小鼠中，约20%浸润胰腺的CD4 + T细胞产生干扰素-γ（IFN-γ），而产生白细胞介素-10（IL-10）或白细胞介素-4（IL-4）的细胞极少，这表明IDDM与靶器官中的1型T细胞浸润有关。正如胰腺浸润T细胞上P-选择素配体表达增加所显示的那样，IL-12缺陷型NOD小鼠胰腺中的T细胞募集似乎更为有利，这至少在一定程度上可以弥补从外周淋巴器官募集的Th1细胞池的缺陷。与用IL-12拮抗剂处理的野生型NOD小鼠不同，由于未诱导产生Th2细胞，IL-12缺陷型NOD小鼠的胰腺中也会积累残余的Th1细胞。因此，在多基因控制下的自发性慢性进行性自身免疫性疾病（如IDDM）中，似乎需要一种调节途径来对抗在缺乏IL-12的情况下发育的致病性Th1细胞。
