Multiple immuno-regulatory defects in type-1 diabetes
Multiple immuno-regulatory defects in type-1 diabetes
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DOI：
10.1172/jci13605
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发表时间：
2002-01-01
影响因子：
15.9
通讯作者：
Maclaren, N
中科院分区：
文献类型：
--
作者：
Kukreja, A;Cost, G;Maclaren, N
人类和NOD小鼠对免疫介导型糖尿病（IMD）的易感性与其固有缺陷的T细胞免疫调节能力有关。我们跟踪了IMD患者的自然杀伤（NK） T细胞数量，通过流式细胞术使用单克隆抗体检测该细胞亚型T细胞受体中发现的特征连接，并通过半定量RT-PCR检测相应转录本。在临床发病前后，这些细胞在患者PBMCs中的表现都有所减少。我们还报道了IMD患者的静息CD4(+) CD25(+) T细胞数量低，这是一种T细胞亚群，在3天胸腺去化实验小鼠中具有重要的免疫调节功能。尽管Th1和Th2细胞因子的偏倚被认为是这两个物种IMD发病机制的基础，但我们发现，在我们的患者中，在体外用磷酚-肉芽酸酯和离子霉素刺激其PBMCs后，ifn - γ产生缺陷，并且在Valpha24(+) NK t富集细胞中存在ifn - γ和IL-4缺陷。这些数据表明，多种免疫调节性T （Treg）细胞缺陷是导致人类IMD的胰岛细胞自身免疫的基础，这些病变可能是广泛T细胞缺陷的一部分。
Susceptibility to immune-mediated diabetes (IMD) in humans and NOD mice involves their inherently defective T cell immunoregulatory abilities. We have followed natural killer (NK) T cell numbers in patients with IMD, both by flow cytometry using mAbs to the characteristic junctions found in the T cell receptors of this cell subtype, and by semiquantitative RT-PCR for the corresponding transcripts. Both before and after clinical onset, the representation of these cells in patients' PBMCs is reduced. We also report low numbers of resting CD4(+) CD25(+) T cells in IMD patients, a subset of T cells shown to have important immunoregulatory functions in abrogating autoimmunities in 3-day thymectomized experimental mice. Whereas a biased Th1 to Th2 cytokine profile has been suggested to underlie the pathogenesis of IMD in both species, we found defective production of IFN-gamma in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-gamma and IL-4 deficiencies in Valpha24(+) NK T-enriched cells. These data suggest that multiple immunoregulatory T (Treg) cell defects underlie islet cell autoimmunity leading to IMD in humans and that these lesions may be part of a broad T cell defect.