Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus
Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus
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DOI：
10.1172/jci200317165
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发表时间：
2003-10-01
影响因子：
15.9
通讯作者：
Strober, S
中科院分区：
文献类型：
--
作者：
Zeng, DF;Liu, YP;Strober, S
用自然杀伤T（NKT）细胞配体，a.-半乳糖神经酰胺（alphaGalCer）通过将致病性Th 1型免疫应答转变为非致病性Th 2型应答来改善自身免疫性糖尿病和实验性自身免疫性脑脊髓炎（EAE）。在本研究中，通过多次注射α GalCer在成年NZB/W小鼠中体内激活NKT细胞，与在非自身免疫性C57 BL/6小鼠中观察到的Th 2型应答相比，诱导了异常的Th 1型免疫应答。这导致血清IgE水平降低，IgG 2a和IgG 2a抗双链DNA（抗dsDNA）Ab水平升高，并加重狼疮。相反，用阻断性抗CD 1d mAb治疗NZB/W小鼠增强了Th 2型应答，增加了血清IgE水平，降低了IgG 2a和IgG 2a抗dsDNA Ab的水平，并改善了狼疮。虽然总的CD 4（+）T细胞在体外显著增加脾B细胞的IgM抗dsDNA Ab分泌，但非CD 1d反应性（CD 1d-alphaGalCer四聚体阴性）CD 4（+）T细胞（占所有CD 4（+）T细胞的95%）未能增加Ab分泌。CD 1d反应性四聚体阳性CD 4（+）T细胞使抗dsDNA抗体分泌增加约10倍。总之，NKT细胞的激活增强了Th 1型免疫应答和自身抗体分泌，这有助于成年NZB/W小鼠狼疮的发展，抗CD 1d mAb可能用于治疗狼疮。
In vivo treatment of mice with the natural killer T (NKT) cell ligand, a.-galactosylceramide (alphaGalCer), ameliorates autoimmune diabetes and experimental autoimmune encephalomyelitis (EAE) by shifting pathogenic Th1-type immune responses to nonpathogenic Th2-type responses. In the current study, in vivo activation of NKT cells in adult NZB/W mice by multiple injections of alphaGalCer induced an abnormal Th1-type immune response as compared with the Th2-type response observed in nonautoimmune C57BL/6 mice. This resulted in decreased serum levels of IgE, increased levels of IgG2a and IgG2a anti-double-stranded DNA (anti-dsDNA) Ab's, and exacerbated lupus. Conversely, treatment of NZB/W mice with blocking anti-CD1d mAb augmented Th2-type responses, increased serum levels of IgE, decreased levels of IgG2a and IgG2a anti-dsDNA Ab's, and ameliorated lupus. While total CD4(+) T cells markedly augmented in vitro IgM anti-dsDNA Ab secretion by splenic B cells, the non-CD1d-reactive (CD1d-alphaGalCer tetramer-negative) CD4(+) T cells (accounting for 95% of all CD4(+) T cells) failed to augment Ab secretion. The CD1d-reactive tetramer-positive CD4(+) T cells augmented anti-dsDNA Ab secretion about tenfold. in conclusion, activation of NKT cells augments Th1-type immune responses and autoantibody secretion that contribute to lupus development in adult NZB/W mice, and anti-CD1d mAb might be useful for treating lupus.