Iwai Hideyuki, Abe Masaaki, Hirose Sachiko, Tsushima Fumihiko, Tezuka Katsunari, Akiba Hisaya, Yagita Hideo, Okumura Ko, Kohsaka Hitoshi, Miyasaka Nobuyuki, Azuma Miyuki
Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan.
J Immunol. 2003 Sep 15;171(6):2848-54. doi: 10.4049/jimmunol.171.6.2848.
Inducible costimulator (ICOS)-B7 homologous protein (B7h) is a new member of the CD28-B7 family of costimulatory molecules that regulates T cell-dependent humoral immune responses. In this study, we examined the involvement of this costimulatory pathway in the development and progression of lupus in NZB/W F(1) mice. Expression of ICOS on T cells was enhanced with disease progression, whereas B7h expression on B cells was down-regulated. Administration of anti-B7h mAb before the onset of renal disease significantly delayed the onset of proteinuria and prolonged survival. Blockade of B7h effectively inhibited all subclasses of IgG autoantibody production and accumulation of both Th1 and Th2 cells. Hypercellularity and deposition of IgG and C3 in glomeruli were significantly reduced. B7h blockade after the onset of proteinuria prevented the disease progression and improved the renal pathology. Our results demonstrated the involvement of the ICOS-B7h costimulatory pathway in the pathogenesis of lupus nephritis, and the blockade of this pathway may be beneficial for the treatment of human systemic lupus erythematosus.
诱导性共刺激分子（ICOS）-B7同源蛋白（B7h）是共刺激分子CD28-B7家族的新成员，可调节T细胞依赖性体液免疫反应。在本研究中，我们检测了该共刺激途径在NZB/W F(1)小鼠狼疮发生和发展中的作用。随着疾病进展，T细胞上ICOS的表达增强，而B细胞上B7h的表达下调。在肾病发作前给予抗B7h单克隆抗体可显著延迟蛋白尿的发作并延长生存期。阻断B7h可有效抑制IgG自身抗体产生的所有亚类以及Th1和Th2细胞的积聚。肾小球中细胞增多以及IgG和C3的沉积显著减少。蛋白尿发作后阻断B7h可防止疾病进展并改善肾脏病理。我们的结果表明ICOS-B7h共刺激途径参与了狼疮性肾炎的发病机制，阻断该途径可能对治疗人类系统性红斑狼疮有益。
