Okano Kazuhiro, Nitta Kosaku, Ogawa Shuhei, Horita Shigeru, Habiro Katsuyoshi, Nihei Hiroshi, Abe Ryo
Department of Medicine, Kidney Center, Tokyo Women's Medical University, Kawada-cho, Shinjuku-ku, Japan.
J Lab Clin Med. 2004 Oct;144(4):183-92. doi: 10.1016/j.lab.2004.06.004.
Inducible costimulator (ICOS) is the third member of the CD28 superfamily, expressed on antigen-primed T-cells, enhancing Th2 differentiation. Anti-glomerular basement membrane (anti-GBM) glomerulonephritis results from multiple effects generated by both Th1 and Th2 cells. To evaluate the contribution of these T-cells to the progression of anti-GBM glomerulonephritis, we investigated the effect of double blockade of CD28 and ICOS signaling. Anti-GBM glomerulonephritis was induced in C57BL/6 mice, a Th1-prone strain. CD28 signaling was inhibited with the use of fusion proteins of cytolytic T-lymphocyte-associated antigen-4 (CTLA4 immunoglobulin) and ICOS signaling by the monoclonal antibody (mAb) for ICOS. Blood and urine samples were collected 5 and 14 days after induction of anti-GBM glomerulonephritis. Mice were killed to facilitate histopathologic analyses at the same time. Anti-GBM glomerulonephritis was prevented from functionally deteriorating (eg, proteinuria or increasing serum creatinine) by CTLA4 immunoglobulin or anti-activation-inducible lymphocyte immunomodulatory molecule (AILIM) mAb as an anti-ICOS mAb. Nevertheless, double or single blockade of ICOS signaling showed a weaker inhibitory effect than single blockade of CD28 signaling in terms of the serum immunoglobulin level and histopathologic change. There is no synergistic effect between CTLA4 immunoglobulin and anti-AILIM mAb when simultaneously administered in experimental anti-GBM glomerulonephritis. Double blockade of both CD28 signaling and ICOS signaling is effective for preventing functional deterioration in this model. However, CD28 single blockade is more effective than double blockade both serologically and histopathologically.
诱导性共刺激分子（ICOS）是CD28超家族的第三个成员，表达于抗原致敏的T细胞上，可增强Th2分化。抗肾小球基底膜（抗GBM）肾小球肾炎是由Th1和Th2细胞产生的多种效应所致。为评估这些T细胞对抗GBM肾小球肾炎进展的作用，我们研究了CD28和ICOS信号双阻断的效果。在Th1倾向的C57BL/6小鼠中诱导抗GBM肾小球肾炎。使用细胞毒性T淋巴细胞相关抗原4（CTLA4免疫球蛋白）融合蛋白抑制CD28信号，使用针对ICOS的单克隆抗体（mAb）抑制ICOS信号。在诱导抗GBM肾小球肾炎后5天和14天采集血液和尿液样本。同时处死小鼠以利于进行组织病理学分析。CTLA4免疫球蛋白或抗激活诱导淋巴细胞免疫调节分子（AILIM）mAb（作为抗ICOS mAb）可防止抗GBM肾小球肾炎功能恶化（如蛋白尿或血清肌酐升高）。然而，就血清免疫球蛋白水平和组织病理学变化而言，ICOS信号的双阻断或单阻断显示出比CD28信号单阻断更弱的抑制作用。在实验性抗GBM肾小球肾炎中同时给予CTLA4免疫球蛋白和抗AILIM mAb时没有协同效应。CD28信号和ICOS信号的双阻断对预防该模型中的功能恶化有效。然而，在血清学和组织病理学方面，CD28单阻断比双阻断更有效。
