免疫病の分子・遺伝子治療に関する研究

1993-1996年间，在特别促进研究资助计划的支持下进行的研究取得了以下具有代表性的成果：i)阐明了通过IL-6受体和gp130进行的信号转导的轮廓，即已确定了两条信号通路，即a)JAK-STAT3/APRF途径和b)RAS-Map激酶级联和激活NF-IL6。ii)靶向干扰参与细胞因子信号转导的基因，揭示了gp130、STAT3、STAT6和NF-IL6等信号分子在体内迄今未知的功能。NFIL6基因敲除小鼠对李斯特菌感染完全敏感，揭示了NFIL6在巨噬细胞杀菌活性中的重要作用。Gp130基因敲除是致命的，心肌发育受到损害，揭示了通过gp130信号对心肌发育和防止细胞凋亡的重要作用。iii)前B细胞发育的关键因子之一的趋化因子(PBSF/SDF-1)及其受体已被克隆，结果表明PBSF/SDF-1的受体作为HIV辅助受体发挥功能。iv)编码B淋巴细胞激活的辅助受体CD40和CD23的基因已被敲除，并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性治疗，用人源化的抗IL-6受体抗体治疗Castleman病和类风湿性关节炎，证实了其疗效。

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.