免疫病の分子・遺伝子治療に関する研究

1993-1996年期间在特别促进研究补助金支助下进行的研究取得的代表性成果如下：i）已经阐明了通过IL-6受体和gp 130的信号转导的概述，即已经鉴定了两种信号传导途径，即a）JAK-STAT 3/APRF途径和B）Ras-Map激酶级联和NF-IL 6的活化。ii）参与细胞因子信号传导的基因的靶向破坏揭示了迄今未知的信号传导分子如gp 130，STAT 3，STAT 6和NF-IL 6。NF-IL 6基因敲除小鼠对李斯特菌感染完全敏感，揭示了NF-IL 6在巨噬细胞杀菌活性中的重要作用。gp 130基因敲除是致死性的，心肌发育是不稳定的，揭示了通过gp 130的信号对于心肌发育和防止细胞凋亡的重要作用。（PBSF/SDF-1）及其受体是前B细胞发育的必需因子之一，已经克隆了PBSF/SDF-1的受体，结果显示PBSF/SDF-1的受体作为HIV辅助受体起作用，fusin.iv）编码B淋巴细胞活化的辅助受体CD 40和CD 23的基因已经被敲除，并且揭示了这些分子在体液和T细胞依赖性细胞免疫中的体内作用。v）多发性骨髓瘤患者的实验治疗，Castleman病和类风湿性关节炎与人源化抗-IL-6受体抗体的研究已经开展，并证实了其对这些疾病的有效性。

Representative results which have been obtained by the studies done between 1993-1996 under the support by the Grant-in-Aid for Specially Promoted Research are as follows ;i) Outline of the signal transduction through IL-6 receptor and gp130 has been elucidated, i.e.two signalling pathways have been identified, namely a) JAK-STAT3/APRF pathway and b) Ras-Map kinase cascade and activation of NF-IL6.ii) Targetted disruption of the genes inyolved in the cytokine signalling revealed the hitherto unknown in vivo function of the signalling molecules such as gp130, STAT3, STAT6 and NF-IL6. NF-IL6 knockout mice were completely sensitive to Listeria infection, revealing the essential role of NF-IL6 in bactericidal activity of macrophage. gp130 knockout was lethal and cardiac muscle development was impared, revealing the essential role of the signals through gp130 for cardiac muscle development and prevention of apoptosis.iii) A chemokine (PBSF/SDF-1) and its receptor which are one of the essential factor for pre B cell development, have been cloned and the results have revealed that a receptor for PBSF/SDF-1 functions as a HIV coreceptor, fusin.iv) The genes encoding coreceptors for B lymphocyte activation, CD40 and CD23 have been knocked out and in vivo roles of these molecules in humoral and T cell-dependent cellular immunity are revealed.v) Experimental treatments of patients with multiple myeloma, Castleman's disease and rheumatoid arthritis with humanized anti-IL6 receptor antibody have been carried out and its effectiveness on these diseases are confirmed.