类风湿关节炎相关细胞因子及药物研究进展
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摘要
类风湿关节炎(Rheumatoid Arthritis,RA)是一种导致关节破坏的慢性系统性自身免疫炎症性疾病,在关节滑膜中的免疫调节破坏、关节的进行性破坏、导致软骨和骨侵蚀的严重损伤是这种疾病的主要特征。细胞因子在其发病机制中起关键作用,细胞因子网络的不平衡可能诱导和维持炎症以及相应的组织损伤,从而提供治疗的靶点。RA中涉及许多细胞因子,文章综述了一些关键细胞因子,包括肿瘤坏死因子(TNF-α)、白细胞介素家族(IL-6、IL-1、IL-17和IL-35)和粒细胞-巨噬细胞集落刺激因子(GM-CSF)。靶向TNF-α和IL-6都是公认的RA治疗方法,并且不断有新的生物制剂正在进入市场。IL-1是细胞因子网络中复杂的细胞因子,IL-1受体拮抗剂的临床治疗效果不如TNF-α抑制剂。IL-17、GM-CSF和IL-35是代表新靶标的细胞因子,其抑制剂作为RA治疗开发的第二代生物制剂。
Rheumatoid arthritis( RA) is a chronic systemic autoimmune inflammatory disease. Its main features of the disease include the destruction of immune regulation in joint synovium,progressive destruction of the joint,and severe damage to cartilage,bone erosion and so on. Cytokines play a key role in RA pathogenesis,and imbalances in cytokine networks may induce and maintain inflammation and corresponding tissue damage. Thereby,the target of treatment is provided. Several RA related key cytokines are reviewed in this paper,including tumor necrosis factor( TNF-α),Interleukin family( IL-6,IL-1,IL-17 and IL-35) or Granulocytemacrophage colony-stimulating factor( GM-CSF). Targeting TNF-α and IL-6 is recognized treatment for RA,and new biologics are constantly entering the market. IL-1 is one member in the cytokine network that plays complex functions,and the clinical efficacy of IL-1 receptor antagonists is worse than that of TNF-alpha inhibitors. IL-17,GM-CSF and IL-35 are cytokines representing new targets,and their inhibitors are the second generation biologics developed for RA treatment.
Rheumatoid arthritis( RA) is a chronic systemic autoimmune inflammatory disease. Its main features of the disease include the destruction of immune regulation in joint synovium,progressive destruction of the joint,and severe damage to cartilage,bone erosion and so on. Cytokines play a key role in RA pathogenesis,and imbalances in cytokine networks may induce and maintain inflammation and corresponding tissue damage. Thereby,the target of treatment is provided. Several RA related key cytokines are reviewed in this paper,including tumor necrosis factor( TNF-α),Interleukin family( IL-6,IL-1,IL-17 and IL-35) or Granulocytemacrophage colony-stimulating factor( GM-CSF). Targeting TNF-α and IL-6 is recognized treatment for RA,and new biologics are constantly entering the market. IL-1 is one member in the cytokine network that plays complex functions,and the clinical efficacy of IL-1 receptor antagonists is worse than that of TNF-alpha inhibitors. IL-17,GM-CSF and IL-35 are cytokines representing new targets,and their inhibitors are the second generation biologics developed for RA treatment.
引文
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[11] Garlanda C,Dinarello CA,Mantovani A. The Interleukin-1 Family:Back to the Future[J]. Immunity,2013,39(6):1003-1018.
[12] Merhi-Soussi F,Berti M,Wehrle-Haller B,et al. Intracellular interleukin-1 receptor antagonist type 1 antagonizes the stimulatory effect of interleukin-1αprecursor on cell motility[J]. Cytokine,2005,32(3-4):163-170.
[13] Mertens M,Singh JA. Anakinra for rheumatoid arthritis[J]. J Rheumatol,2009,36(6):1118-1125.
[14] Gaffen SL. Structure and signalling in the IL-17 receptor family[J]. Nat Rev Immunol,2009,9(11):556-567.
[15] Agarwal S,Misra R,Aggarwal A. Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases[J]. J Rheumatol,2008,35(3):515-519.
[16] Adamopoulos IE,Chao C,Geissler R,et al. Interleukin-17A upregulates receptor activator of NF-κB on osteoclast precursors[J]. Arthritis Res Ther,2010,12(1):1-11.
[17] Nakae S,Nambu A,Sudo K,et al. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice[J]. J Immunol,2003,171(11):6173-6177.
[18] Pope RM,Shahrara S. Possible roles of IL-12-family cytokines in rheumatoid arthritis[J]. Nat Rev Rheumatol,2013,9(4):252-256.
[19] Kochetkova I,Golden S,Holderness K,et al. IL-35 Stimulation of CD39+regulatory T cells confers protection against collagen IIinduced arthritis via the production of IL-10[J]. J Immunol,2010,184(12):7144-7153.
[20] Shetty A,Hanson R,Korsten P,et al. Tocilizumab in the treatment of rheumatoid arthritis and beyond[J]. Drug Des Devel Ther,2014,8(4):349-364.
[21] Wicks IP,Roberts AW. Targeting GM-CSF in inflammatory diseases[J]. Nat Rev Rheumatol,2016,12(1):37-48.
[22] Hercus TR,i Dhagat U,Kan WLT,et al. Signalling by the beta c family of cytokines[J]. Cytokine Grow Fact Rev,2013,24(3):189-201.
[23] Bunda S,Kang MW,Sybingco SS,et al. Inhibition of SRC corrects GM-CSF hypersensitivity that underlies juvenile myelomonocytic leukemia[J]. Cancer Res,2013,73(8):2540-2550.
[24] Shiomi A,Usui T,Mimori T. GM-CSF as a therapeutic target in autoimmune diseases[J]. Inflamm Regen,2016,36(1):1-9.
[25] Burmester GR,Mcinnes IB,Kremer J,et al. A randomised phase IIb study of mavrilimumab,a novel GM-CSF receptor alpha monoclonal antibody,in the treatment of rheumatoid arthritis[J]. Ann Rheum Dis,2017,76(6):1020-1030.
[26] Isomaki P,Junttila I,Vidqvist KL,et al. The activity of JAK-STAT pathways in rheumatoid arthritis:constitutive activation of STAT3correlates with interleukin 6 levels[J]. Rheumatol,2015,54(6):1103-1113.
[27] O'Shea JJ,Schwartz DM,Villarino AV,et al. The JAK-STAT pathway:impact on human disease and therapeutic intervention[J]. Ann Rev Med,2015,66(1):311-328.
[28] De Oliveira RA,Fierro IM,Barreiro EJDL,et al. New strategies for patenting biological medicines used in rheumatoid arthritis treatment[J]. Expert Opin Ther Pat,2018,28(8):635-646.
[29] Rein P,Mueller RB. Treatment with biologicals in rheumatoid arthritis:an overview[J]. Rheumatol Ther,2017:1-15.
[2] Noack M,Miossec P. Selected cytokine pathways in rheumatoid arthritis[J]. Seminars Immunopathol,2017:1-19.
[3] Kalliolias GD,and Ivashkiv LB. TNF biology,pathogenic mechanisms and emerging therapeutic strategies[J]. Nat Rev Immunol,2016,12(1):49.
[4] Osta B,Lavocat F,Eljaafari A,et al. Effects of interleukin-17A on osteogenic differentiation of isolated human mesenchymal stem cells[J]. Front Immunol,2014,5:425.
[5] Taylor PC,Peters AM,Paleolog E,et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factorαblockade in patients with rheumatoid arthritis[J]. Arth Rheum,2000,43(1):38-47.
[6] Hess A,Axmann R,Rech J,et al. Blockade of TNF-αrapidly inhibits pain responses in the central nervous system[J]. Proc Nat Acad Sci USA,2011,108(9):3731-3736.
[7] Atzeni F,Talotta R,Salaffi F,et al. Immunogenicity and autoimmunity during anti-TNF therapy[J]. Autoimm Rev,2013,12(7):703-708.
[8] Brzustewicz E,and Bryl E. The role of cytokines in the pathogenesis of rheumatoid arthritis-Practical and potential application of cytokines as biomarkers and targets of personalized therapy[J].Cytokine,2015,76(2):527-536.
[9] Hashizume M,Uchiyama Y,Horai N,et al. Tocilizumab,a humanized anti-interleukin-6 receptor antibody,improved anemia in monkey arthritis by suppressing IL-6-induced hepcidin production[J]. Rheumatol Int,2010,30(7):917-923.
[10] Okuda Y,Takasugi K. Successful use of a humanized anti-interleukin-6 receptor antibody,tocilizumab,to treat amyloid A amyloidosis complicating juvenile idiopathic arthritis[J]. Arth Rheum,2014,54(9):2997-3000.
[11] Garlanda C,Dinarello CA,Mantovani A. The Interleukin-1 Family:Back to the Future[J]. Immunity,2013,39(6):1003-1018.
[12] Merhi-Soussi F,Berti M,Wehrle-Haller B,et al. Intracellular interleukin-1 receptor antagonist type 1 antagonizes the stimulatory effect of interleukin-1αprecursor on cell motility[J]. Cytokine,2005,32(3-4):163-170.
[13] Mertens M,Singh JA. Anakinra for rheumatoid arthritis[J]. J Rheumatol,2009,36(6):1118-1125.
[14] Gaffen SL. Structure and signalling in the IL-17 receptor family[J]. Nat Rev Immunol,2009,9(11):556-567.
[15] Agarwal S,Misra R,Aggarwal A. Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases[J]. J Rheumatol,2008,35(3):515-519.
[16] Adamopoulos IE,Chao C,Geissler R,et al. Interleukin-17A upregulates receptor activator of NF-κB on osteoclast precursors[J]. Arthritis Res Ther,2010,12(1):1-11.
[17] Nakae S,Nambu A,Sudo K,et al. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice[J]. J Immunol,2003,171(11):6173-6177.
[18] Pope RM,Shahrara S. Possible roles of IL-12-family cytokines in rheumatoid arthritis[J]. Nat Rev Rheumatol,2013,9(4):252-256.
[19] Kochetkova I,Golden S,Holderness K,et al. IL-35 Stimulation of CD39+regulatory T cells confers protection against collagen IIinduced arthritis via the production of IL-10[J]. J Immunol,2010,184(12):7144-7153.
[20] Shetty A,Hanson R,Korsten P,et al. Tocilizumab in the treatment of rheumatoid arthritis and beyond[J]. Drug Des Devel Ther,2014,8(4):349-364.
[21] Wicks IP,Roberts AW. Targeting GM-CSF in inflammatory diseases[J]. Nat Rev Rheumatol,2016,12(1):37-48.
[22] Hercus TR,i Dhagat U,Kan WLT,et al. Signalling by the beta c family of cytokines[J]. Cytokine Grow Fact Rev,2013,24(3):189-201.
[23] Bunda S,Kang MW,Sybingco SS,et al. Inhibition of SRC corrects GM-CSF hypersensitivity that underlies juvenile myelomonocytic leukemia[J]. Cancer Res,2013,73(8):2540-2550.
[24] Shiomi A,Usui T,Mimori T. GM-CSF as a therapeutic target in autoimmune diseases[J]. Inflamm Regen,2016,36(1):1-9.
[25] Burmester GR,Mcinnes IB,Kremer J,et al. A randomised phase IIb study of mavrilimumab,a novel GM-CSF receptor alpha monoclonal antibody,in the treatment of rheumatoid arthritis[J]. Ann Rheum Dis,2017,76(6):1020-1030.
[26] Isomaki P,Junttila I,Vidqvist KL,et al. The activity of JAK-STAT pathways in rheumatoid arthritis:constitutive activation of STAT3correlates with interleukin 6 levels[J]. Rheumatol,2015,54(6):1103-1113.
[27] O'Shea JJ,Schwartz DM,Villarino AV,et al. The JAK-STAT pathway:impact on human disease and therapeutic intervention[J]. Ann Rev Med,2015,66(1):311-328.
[28] De Oliveira RA,Fierro IM,Barreiro EJDL,et al. New strategies for patenting biological medicines used in rheumatoid arthritis treatment[J]. Expert Opin Ther Pat,2018,28(8):635-646.
[29] Rein P,Mueller RB. Treatment with biologicals in rheumatoid arthritis:an overview[J]. Rheumatol Ther,2017:1-15.