わかりやすいRAサイトカインのネットワーク

1 ( IL-1 IL-6 IL-2/IL-4 IFNg IL-10 (1) IL-1 IFN-IL-6IL-2, IL-4 Disease activity0123456789101112 (day)IL-10 I(IL-2, IL-3, IL-6, IL-12, G-CSF II(IFN, IL-10, IL-22 IL-1 (IL-1, IL-18 TNF/Fas TGF- ( ) (IL) : IL-1, 2, 3, 4---------26 (IFN): a, b, g (TNF): a, b (TGF): a, b (CSF).))))

2 G, GM, M RA ( ) , , ( ) Th1Th2 IFN- +/-++IgE-++GM-CSF+++IL-2+++/-IL-6++-IL-5 ++-IL-4++-IgG2A+++IL-3++++ 5 (1980~90 ) T IL-2 IFNg IL-4,IL-5,IL-6 Th1 Th2 (2) ( ( T Th1 Th2 TNF IL-6 RA ( 4 ( ))))

3 ( IL-2 CD4 IL-10 IL-4 IL-13 RA Th1 T (5) Th17 IL-6 TNF-IL-1 GM-CSFIL-8 MIP1IL-1ra IL-10RA RA RA T IL-2IL-4 IFN-IL-10IL-4IL-5IL-2 LTIFN-IgG2aIgEIL-3IL-4 MMast cellT cellEosinophilIFN-IL-5Th1Th2 Th1/Th2 4RA 2RA IL-10 ( ) 3 TNFIL-1IL-6IL-8(pg/ml)(pg/ml)(ng/ml)(ng/ ml))

4 Day1control1,145 418 1,708 85 135 63227 77IL-10563 210 1,098 725 125 56200 69 Day3control 301 133 1,563 1,168 248 86479 147IL-10106 36 1,317 1,041 242 83 449 135 Day5control 185 100 407 147 241 65438 100IL-1055 24 204 89 231 60 308 76 TNFIL-1IL-6IL-8(pg/ml)(pg/ml)(ng/ml)(ng/ ml) Day1isotype control 1,168 380 1,542 660142 56258 79anti-IL-102,236 649 2,899 991 160 61271 76 Day3isotype control 295 134 1,761 1,284 276 83510 161anti-IL-10 1,025 5052,513 1,665 280 80514 142 Day5isotype control 173 92 381 210 282 73419 95anti-IL-10 1,024 781 1,170 516 272 59535 121RA anti-IL-10 IL-10 RA IL-10 IL-10 T (3,4)

5 TNF IL-6IL-1 (MTX) TNF TNF TNF IL-6 3RA IL-6 RA anti-IL-10 RA IL-10 TNFa IL-6 RA ( 3) (5) RA 6 T VEGF RF T CRP 6 SKG DNA (12) SKG CD4+T T T/B SCID IL-6, IL-4, IFNg, IL-17 SKG IL-6 IL-17 Th1, Th2 Th17 SPF (specific pathogen free) (non SPF) (13)

6 IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17, IL-21, IL-23, TNF, TGF IL-17 T Th1 Th2 IL-17 T Th1 Th2 Th17 TNF, IL-21, IL-22 Th1 Th2 T-bet,GATA3, STAT Th17 Th17 (6,7,8,9)) IL-17 (A-F) IL-17 (10) IL-17 (11) IL-10 TGF- ThpTh1Th2IL-12IL-4Th17IL-17IL-17 FIL-22IL-21 TregIL-2IL-25IL-27IL-23IL-1 GATA3 STAT6IL-4 IFN-Foxp3 STAT5IL-6IL-2 TGF-IL-6 IL-21) T-betSTAT 1 STAT4 TGF- 7 Th1/Th2/Th17 Treg (14) 8RA IL-17/Th17 9 15 020406080100120140 BIRB 796SB220025 PSLIL-6 (% of contorol)100nM1000nM 9 (16,17,18) JAK3 IL-2, IL-4, IL-7, IL-9, IL-15 IL-21 2008 ACR RA JAK3 CP690550 10 (19) JAK3 JAK (JAK1, JAK2, Tyk2)

7 MTX RA 11 P38 MAPK RA IL-6 10 JAK3 10203040506070 ACR20 ACR50 ACR70 DAS28remission0 Placebo1mg3mg5mg10mg15mg20mg384959616059 6017243137314736672218132524973218303825 (%)CP690550n= of cytokine mRNA expression in the central nervous system of mice et al. J ; 149: 2496-2505 types of murine helper T cell clone. I. Definition according to profiles et al.

8 J ; 136: PD et al. J. Exp. Med. 179, 1517-1527, L et al. A randomized, double blind, placebo controlled multicenter trial of murine anti-CD4 monoclonal antibody therapy in rheumatoid arthritis. J Rheumatol. 1998 Aug;25(8):1457-61. EH., Isenberg DA., Garrood T., et benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation ; 46 CT., Hatton RD., Mangan PR., et al. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007; 25 LE., Hatton RD., Mangan PR., et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 Immunol.

9 2005; 6 H., Li Z., Tang XO., et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat ; 6 T., Bettelli E., Gao W., et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 2007; 448 S., Nambu A., Sudo K., et of immune induction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol. 2003; 171 E., Koenders MI., Oppers-Walgreen B., et al. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation,cartilage destruction, and bone erosion. Arthritis ; 50 N., Takahashi T, Hata H et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.

10 Nature 2003; 426: H., Sakaguchi N., Kobayashi K., et role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible Exp ; 201 Lubberts Review ArticleIL-17/Th17 targeting: On the road to prevent chronic destructive arthritis?Cytokine 41 (2008)84-9115. 2007 3 , O Shea Jaks and STATs :biological implications. Annu. Rev. Immunol. 16:293-322, K., Min B., Zhou YJ., et negatively regulates dendritic cell cytokine production and survival. Blood 2005; 106 M., Laurence A., Kishore N., et al. Therapeutic targeting of Janus kinases. Immunol ; 223 JM, Cohen S., B. Wilkinson et al: The Oral Jak Inhibitor CP-690,550 (CP) in combination with Methotrexate (MTX) is Efficacious, Safe and Well Tolerated in Patients with Active Rheumatoid Arthiritis (RA) with an Inadequate Response to Methotrexate Alone.