Establishment of the anti-IL-6 receptor therapy for refractory autoimmune diseases

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We have confirmed the efficacy of an anti-Interleukin-6 (IL-6) receptor antibody, tocilizumab, for rheumatoid arthritis (RA) and systemic-onset juvenile idiopathic arthritis (soJIA). IL-6 blockade increased serum androgen which has anti-inflammatory effect for RA. IL-6 blockade also retarded the progression of joint damage and the long-term efficacy was predicted by the decrease in the serum MMP-3, CRP and PIIANP in the first 3 months after the start of tocilizumab. In the patients with soJIA, an exhaustive DNA microarray analysis of mRNA expression revealed 24 molecules differentially expressed compared to healthy donors. Those included the molecules related to innate immunity, signal transduction and cell growth. Gene Ontology and Network, Pathway analysis also revealed the stimulation of IFN-γ, TNF cascades in both soJIA and polyarticular JIA. ATP synthesis related genes were down-regulated only in soJIA. These molecules might play a pathological role in soJIA. We are now studying a pathological role in relation to IL-6. In systemic lupus erythematosus (SLE), DNA microarray analysis identified 24 molecules which include 9 IFN-α-inducible genes and defensin-α3. We have also established new receptor inhibitor of IL-6 (NRI) which is feasible to gene therapy.We have identified several candidate molecules which play pathological roles in these autoimmune diseases. The in vivo functions of them are being studied.