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Successes and failures of chemokine-pathway targeting in rheumatoid arthritis

Nature Reviews Rheumatology volume 12, pages 5–13 (2016)Cite this article

Subjects

Key Points

  • Chemokines and chemokine receptors have been implicated in leukocyte recruitment and angiogenesis underlying rheumatoid arthritis (RA) and other inflammatory rheumatic diseases

  • Chemokines and chemokine receptors are abundant in the synovium and other inflammatory sites

  • Promising results from preclinical studies of agents targeting chemokines and chemokine receptors in animal models of arthritis have not been replicated in human trials of antibodies and synthetic compounds in RA

  • Possible reasons for the lack of positive results from human trials include pathway redundancy, incomplete antagonism and interspecies differences that limit translation of results from animal models

  • An alternative approach to the targeting of individual chemokines is chemokine-receptor blockade

  • The CCR1 receptor is a potential target, assuming that a high level of receptor occupancy can be maintained throughout treatment

Abstract

Chemokines and chemokine receptors are involved in leukocyte recruitment and angiogenesis underlying the pathogenesis of rheumatoid arthritis (RA) and other inflammatory rheumatic diseases. Numerous chemokines, along with both conventional and atypical cell-surface chemokine receptors, are found in inflamed synovia. Preclinical studies carried out in animal models of arthritis involving agents targeting chemokines and chemokine receptors have yielded promising results. However, most human trials of treatment of RA with antibodies and synthetic compounds targeting chemokine signalling have failed to show clinical improvements. Chemokines can have overlapping actions, and their activities can be altered by chemical modification or proteolytic degradation. Effective targeting of chemokine pathways must take acount of these properties, and can also require high levels of receptor occupancy by therapeutic agents to prevent signalling. CCR1 is a promising target for chemokine-receptor blockade.

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Figure 1: Leukocyte trafficking into the inflamed synovium.
Figure 2: Known interactions between chemokines and their receptors.

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References

  1. Szekanecz, Z., Vegvari, A., Szabo, Z. & Koch, A. E. Chemokines and chemokine receptors in arthritis. Front. Biosci. (Schol. Ed.) 2, 153–167 (2010).

    Article  Google Scholar 

  2. Szekanecz, Z., Koch, A. E. & Tak, P. P. Chemokine and chemokine receptor blockade in arthritis, a prototype of immune-mediated inflammatory diseases. Neth. J. Med. 69, 356–366 (2011).

    CAS  PubMed  Google Scholar 

  3. Koch, A. E. Chemokines and their receptors in rheumatoid arthritis: future targets? Arthritis Rheum. 52, 710–721 (2005).

    Article  PubMed  Google Scholar 

  4. Vergunst, C. E. & Tak, P. P. Chemokines: their role in rheumatoid arthritis. Curr. Rheumatol. Rep. 7, 382–388 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Zlotnik, A. & Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity 12, 121–127 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Szekanecz, Z. & Koch, A. E. Chemokines and angiogenesis. Curr. Opin. Rheumatol. 13, 202–208 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Bachelerie, F. et al. International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol. Rev. 66, 1–79 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nibbs, R. J. & Graham, G. J. Immune regulation by atypical chemokine receptors. Nat. Rev. Immunol. 13, 815–829 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Maracle, C. X. & Tas, S. W. Inhibitors of angiogenesis: ready for prime time? Best Pract. Res. Clin. Rheumatol. 28, 637–649 (2014).

    Article  PubMed  Google Scholar 

  10. Snowden, N., Hajeer, A., Thomson, W. & Ollier, B. RANTES role in rheumatoid arthritis. Lancet 343, 547–548 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Koch, A. E. et al. Growth-related gene product alpha. A chemotactic cytokine for neutrophils in rheumatoid arthritis. J. Immunol. 155, 3660–3666 (1995).

    CAS  PubMed  Google Scholar 

  12. Koch, A. E. et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258, 1798–1801 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Koch, A. E. et al. Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis. J. Clin. Invest. 94, 1012–1018 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nanki, T. et al. Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J. Immunol. 165, 6590–6598 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Nanki, T. et al. Pathogenic role of the CXCL16–CXCR6 pathway in rheumatoid arthritis. Arthritis Rheum. 52, 3004–3014 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Manzo, A. et al. Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. Arthritis Rheum. 58, 3377–3387 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Szekanecz, Z. & Koch, A. E. Macrophages and their products in rheumatoid arthritis. Curr. Opin. Rheumatol. 19, 289–295 (2007).

    Article  PubMed  Google Scholar 

  18. Ruth, J. H. et al. Role of macrophage inflammatory protein-3α and its ligand CCR6 in rheumatoid arthritis. Lab. Invest. 83, 579–588 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Iwamoto, T. et al. Monocyte chemoattractant protein-4 (MCP-4)/CCL13 is highly expressed in cartilage from patients with rheumatoid arthritis. Rheumatology (Oxford) 45, 421–424 (2006).

    Article  CAS  Google Scholar 

  20. Haringman, J. J., Smeets, T. J., Reinders-Blankert, P. & Tak, P. P. Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis. Ann. Rheum. Dis. 65, 294–300 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Yeo, L. et al. Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2014-206921 (2015).

  22. Asquith, D. L., Bryce, S. A. & Nibbs, R. J. Targeting cell migration in rheumatoid arthritis. Curr. Opin. Rheumatol. 27, 204–211 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Greisen, S. R. et al. CXCL13 predicts disease activity in early rheumatoid arthritis and could be an indicator of the therapeutic 'window of opportunity'. Arthritis Res. Ther. 16, 434 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Koch, A. E. et al. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J. Clin. Invest. 90, 772–779 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Koch, A. E. et al. Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J. Clin. Invest. 93, 921–928 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pickens, S. R. et al. Characterization of CCL19 and CCL21 in rheumatoid arthritis. Arthritis Rheum. 63, 914–922 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. van Lieshout, A. W. et al. Circulating levels of the chemokine CCL18 but not CXCL16 are elevated and correlate with disease activity in rheumatoid arthritis. Ann. Rheum. Dis. 66, 1334–1338 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen, Z. et al. Characterising the expression and function of CCL28 and its corresponding receptor, CCR10, in RA pathogenesis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2013-204530 (2014).

  29. Pease, J. E. & Horuk, R. Recent progress in the development of antagonists to the chemokine receptors CCR3 and CCR4. Expert Opin. Drug Discov. 9, 467–483 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Volin, M. V. et al. Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis. Am. J. Pathol. 159, 1521–1530 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Volin, M. V., Huynh, N., Klosowska, K., Chong, K. K. & Woods, J. M. Fractalkine is a novel chemoattractant for rheumatoid arthritis fibroblast-like synoviocyte signaling through MAP kinases and Akt. Arthritis Rheum. 56, 2512–2522 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Klareskog, L., Padyukov, L., Rönnelid, J. & Alfredsson, L. Genes, environment and immunity in the development of rheumatoid arthritis. Curr. Opin. Immunol. 18, 650–655 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Yoshida, K. et al. Citrullination of epithelial neutrophil-activating peptide 78/CXCL5 results in conversion from a non-monocyte-recruiting chemokine to a monocyte-recruiting chemokine. Arthritis Rheumatol. 66, 2716–2727 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Qin, S. et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J. Clin. Invest. 101, 746–754 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Petit, I., Jin, D. & Rafii, S. The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol. 28, 299–307 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ruth, J. H. et al. CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway. Arthritis Rheum. 54, 765–778 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Talbot, J. et al. CCR2 expression in neutrophils plays a critical role in their migration into joints in rheumatoid arthritis. Arthritis Rheumatol. 67, 1751–1759 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Pokorny, V. et al. Evidence for negative association of the chemokine receptor CCR5 d32 polymorphism with rheumatoid arthritis. Ann. Rheum. Dis. 64, 487–490 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Hirota, K. et al. Preferential recruitment of CCR6-expressing TH17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J. Exp. Med. 204, 2803–2812 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wengner, A. M. et al. CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum. 56, 3271–3283 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Pingiotti, E. et al. Surface expression of fractalkine receptor (CX3CR1) on CD4+/CD28− T cells in RA patients and correlation with atherosclerotic damage. Ann. NY Acad. Sci. 1107, 32–41 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Patterson, A. M., Siddall, H., Chamberlain, G., Gardner, L. & Middleton, J. Expression of the duffy antigen/receptor for chemokines (DARC) by the inflamed synovial endothelium. J. Pathol. 197, 108–116 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Hansell, C. A. et al. The atypical chemokine receptor ACKR2 suppresses TH17 responses to protein autoantigens. Immunol. Cell Biol. 93, 167–176 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Hall, S. E. et al. Elucidation of binding sites of dual antagonists in the human chemokine receptors CCR2 and CCR5. Mol. Pharmacol. 75, 1325–1336 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Galligan, C. L. et al. Up-regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis. Arthritis Rheum. 50, 1806–1814 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Auer, J. et al. Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis. Arthritis Res. Ther. 9, R94 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tak, P. P. Chemokine inhibition in inflammatory arthritis. Best Pract. Res. Clin. Rheumatol. 20, 929–939 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Haringman, J. J., Oostendorp, R. L. & Tak, P. P. Targeting cellular adhesion molecules, chemokines and chemokine receptors in rheumatoid arthritis. Expert Opin. Emerg. Drugs 10, 299–310 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Loetscher, P., Dewald, B., Baggiolini, M. & Seitz, M. Monocyte chemoattractant protein 1 and interleukin 8 production by rheumatoid synoviocytes. Effects of anti-rheumatic drugs. Cytokine 6, 162–170 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Westermark, P. Skin biopsy in diagnosis of secondary generalized amyloidosis. Nord. Med. 85, 482 (in Swedish) (1971).

    CAS  PubMed  Google Scholar 

  51. Ho, C. Y., Wong, C. K., Li, E. K., Tam, L. S. & Lam, C. W. Suppressive effect of combination treatment of leflunomide and methotrexate on chemokine expression in patients with rheumatoid arthritis. Clin. Exp. Immunol. 133, 132–138 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Volin, M. V., Campbell, P. L., Connors, M. A., Woodruff, D. C. & Koch, A. E. The effect of sulfasalazine on rheumatoid arthritic synovial tissue chemokine production. Exp. Mol. Pathol. 73, 84–92 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Barsig, J., Yam, G., Lehner, M. D. & Beume, R. Methotrexate treatment suppresses local cytokine and chemokine production in rat adjuvant arthritis. Drugs Exp. Clin. Res. 31, 7–11 (2005).

    CAS  PubMed  Google Scholar 

  54. Taylor, P. C. et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor α blockade in patients with rheumatoid arthritis. Arthritis Rheum. 43, 38–47 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Klimiuk, P. A., Sierakowski, S., Domyslawska, I. & Chwiecko, J. Regulation of serum chemokines following infliximab therapy in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 24, 529–533 (2006).

    CAS  PubMed  Google Scholar 

  56. Murphy, P. M. et al. International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol. Rev. 52, 145–176 (2000).

    CAS  PubMed  Google Scholar 

  57. Kawashiri, S. Y. et al. Proinflammatory cytokines synergistically enhance the production of chemokine ligand 20 (CCL20) from rheumatoid fibroblast-like synovial cells in vitro and serum CCL20 is reduced in vivo by biologic disease-modifying antirheumatic drugs. J. Rheumatol. 36, 2397–2402 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Portalès, P. et al. Peripheral blood T4 cell surface CCR5 density as a marker of activity in rheumatoid arthritis treated with anti-CD20 monoclonal antibody. Immunology 128, e738–e745 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Boyle, D. L. et al. The JAK inhibitor tofacitinib suppresses synovial JAK1–STAT signalling in rheumatoid arthritis. Ann. Rheum. Dis. 74, 1311–1316 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Newton, S. M. et al. Reduction of chemokine secretion in response to mycobacteria in infliximab-treated patients. Clin. Vaccine Immunol. 15, 506–512 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Sato, M. et al. Antioxidants inhibit tumor necrosis factor-α mediated stimulation of interleukin-8, monocyte chemoattractant protein-1, and collagenase expression in cultured human synovial cells. J. Rheumatol. 23, 432–438 (1996).

    CAS  PubMed  Google Scholar 

  62. Sato, M., Miyazaki, T., Kambe, F., Maeda, K. & Seo, H. Quercetin, a bioflavonoid, inhibits the induction of interleukin 8 and monocyte chemoattractant protein-1 expression by tumor necrosis factor-α in cultured human synovial cells. J. Rheumatol. 24, 1680–1684 (1997).

    CAS  PubMed  Google Scholar 

  63. Ahmed, S., Pakozdi, A. & Koch, A. E. Regulation of interleukin-1β-induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 54, 2393–2401 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Chen, X., Oppenheim, J. J. & Howard, O. M. Chemokines and chemokine receptors as novel therapeutic targets in rheumatoid arthritis (RA): inhibitory effects of traditional Chinese medicinal components. Cell. Mol. Immunol. 1, 336–342 (2004).

    CAS  PubMed  Google Scholar 

  65. Halloran, M. M. et al. The role of an epithelial neutrophil-activating peptide-78-like protein in rat adjuvant-induced arthritis. J. Immunol. 162, 7492–7500 (1999).

    CAS  PubMed  Google Scholar 

  66. Nanki, T. et al. Inhibition of fractalkine ameliorates murine collagen-induced arthritis. J. Immunol. 173, 7010–7016 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Barnes, D. A. et al. Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J. Clin. Invest. 101, 2910–2919 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Finch, D. K., Ettinger, R., Karnell, J. L., Herbst, R. & Sleeman, M. A. Effects of CXCL13 inhibition on lymphoid follicles in models of autoimmune disease. Eur. J. Clin. Invest. 43, 501–509 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Shahrara, S. et al. Inhibition of monocyte chemoattractant protein-1 ameliorates rat adjuvant-induced arthritis. J. Immunol. 180, 3447–3456 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Zhong, C. et al. Development and preclinical characterization of a humanized antibody targeting CXCL12. Clin. Cancer Res. 19, 4433–4445 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Gong, J. H., Yan, R., Waterfield, J. D. & Clark-Lewis, I. Post-onset inhibition of murine arthritis using combined chemokine antagonist therapy. Rheumatology (Oxford) 43, 39–42 (2004).

    Article  CAS  Google Scholar 

  72. Mohan, K. & Issekutz, T. B. Blockade of chemokine receptor CXCR3 inhibits T cell recruitment to inflamed joints and decreases the severity of adjuvant arthritis. J. Immunol. 179, 8463–8469 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Khan, A., Greenman, J. & Archibald, S. J. Small molecule CXCR4 chemokine receptor antagonists: developing drug candidates. Curr. Med. Chem. 14, 2257–2277 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Barsante, M. M. et al. Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats. Br. J. Pharmacol. 153, 992–1002 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Jehn, C. H. et al. A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection. BMC Immunol. 13, 2 (2012).

    Article  CAS  Google Scholar 

  76. Matthys, P. et al. AMD3100, a potent and specific antagonist of the stromal cell-derived factor-1 chemokine receptor CXCR4, inhibits autoimmune joint inflammation in IFN-γ receptor-deficient mice. J. Immunol. 167, 4686–4692 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Tamamura, H. et al. Identification of a CXCR4 antagonist, a T140 analog, as an anti-rheumatoid arthritis agent. FEBS Lett. 569, 99–104 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Watanabe, K. et al. Pathogenic role of CXCR7 in rheumatoid arthritis. Arthritis Rheum. 62, 3211–3220 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Fabian, C. J. et al. Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator. Clin. Cancer Res. 10, 5403–5417 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Amat, M. et al. Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo. Br. J. Pharmacol. 149, 666–675 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Brühl, H. et al. Targeting of Gr-1+, CCR2+ monocytes in collagen-induced arthritis. Arthritis Rheum. 56, 2975–2985 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Vierboom, M. P. et al. Inhibition of the development of collagen-induced arthritis in rhesus monkeys by a small molecular weight antagonist of CCR5. Arthritis Rheum. 52, 627–636 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Yokoyama, W. et al. Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice. Arthritis Res. Ther. 16, 445 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Plater-Zyberk, C., Hoogewerf, A. J., Proudfoot, A. E., Power, C. A. & Wells, T. N. Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol. Lett. 57, 117–120 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Shahrara, S. et al. Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum. 52, 1907–1919 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhao, Q. Dual targeting of CCR2 and CCR5: therapeutic potential for immunologic and cardiovascular diseases. J. Leukoc. Biol. 88, 41–55 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Haringman, J. J. et al. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum. 54, 2387–2392 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Yellin, M. et al. A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 64, 1730–1739 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Heller, E. A. et al. Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells. Circulation 113, 2301–2312 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Clucas, A. T., Shah, A., Zhang, Y. D., Chow, V. F. & Gladue, R. P. Phase I evaluation of the safety, pharmacokinetics and pharmacodynamics of CP-481,715. Clin. Pharmacokinet. 46, 757–766 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Haringman, J. J., Kraan, M. C., Smeets, T. J., Zwinderman, K. H. & Tak, P. P. Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis. Ann. Rheum. Dis. 62, 715–721 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Vergunst, C. E. et al. MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a Phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study. Arthritis Rheum. 60, 3572–3581 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Naya, A. et al. Structure–activity relationships of xanthene carboxamides, novel CCR1 receptor antagonists. Bioorg. Med. Chem. 11, 875–884 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Santella, J. B. 3rd et al. Discovery of the CCR1 antagonist, BMS-817399, for the treatment of rheumatoid arthritis. J. Med. Chem. 57, 7550–7564 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. US National Library of Medicine. Proof-of-concept study with BMS-817399 to treat moderate to severe rheumatoid arthritis (RA). ClinicalTrials.gov [online], (2013).

  96. Tak, P. P. et al. Chemokine receptor CCR1 antagonist CCX354-C treatment for rheumatoid arthritis: CARAT-2, a randomised, placebo controlled clinical trial. Ann. Rheum. Dis. 72, 337–344 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Dairaghi, D. J. et al. Pharmacokinetic and pharmacodynamic evaluation of the novel CCR1 antagonist CCX354 in healthy human subjects: implications for selection of clinical dose. Clin. Pharmacol. Ther. 89, 726–734 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Lebre, M. C. et al. Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis. PLoS ONE 6, e21772 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Quinones, M. P. et al. The complex role of the chemokine receptor CCR2 in collagen-induced arthritis: implications for therapeutic targeting of CCR2 in rheumatoid arthritis. J. Mol. Med. 83, 672–681 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Horuk, R. Chemokine receptor antagonists: overcoming developmental hurdles. Nat. Rev. Drug Discov. 8, 23–33 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. US National Library of Medicine. Efficacy, tolerability and safety study in rheumatoid arthritis (0812-008). ClinicalTrials.gov [online], (2015).

  102. Vergunst, C. E. et al. Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 58, 1931–1939 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Xue, C. B. et al. Discovery of INCB3284, a potent, selective, and orally bioavailable hCCR2 antagonist. ACS Med. Chem. Lett. 2, 450–454 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gerlag, D. M. et al. Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate. Arthritis Rheum. 62, 3154–3160 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. van Kuijk, A. W. et al. CCR5 blockade in rheumatoid arthritis: a randomised, double-blind, placebo-controlled clinical trial. Ann. Rheum. Dis. 69, 2013–2016 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Fleishaker, D. L. et al. Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial. Arthritis Res. Ther. 14, R11 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Debnath, B., Xu, S., Grande, F., Garofalo, A. & Neamati, N. Small molecule inhibitors of CXCR4. Theranostics 3, 47–75 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Schall, T. J. & Proudfoot, A. E. Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat. Rev. Immunol. 11, 355–363 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Matsukawa, A. et al. Involvement of growth-related protein in lipopolysaccharide-induced rabbit arthritis: cooperation between growth-related protein and IL-8, and interrelated regulation among TNFα, IL-1, IL-1 receptor antagonist, IL-8, and growth-related protein. Lab. Invest. 79, 591–600 (1999).

    CAS  PubMed  Google Scholar 

  110. Verzijl, D. et al. Noncompetitive antagonism and inverse agonism as mechanism of action of nonpeptidergic antagonists at primate and rodent CXCR3 chemokine receptors. J. Pharmacol. Exp. Ther. 325, 544–555 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Zhang, K. et al. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nat. Neurosci. 6, 1064–1071 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. McQuibban, G. A. et al. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 100, 1160–1167 (2002).

    CAS  PubMed  Google Scholar 

  113. Wei, S., Kryczek, I. & Zou, W. Regulatory T-cell compartmentalization and trafficking. Blood 108, 426–431 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Jiao, Z. et al. Accumulation of FoxP3-expressing CD4+CD25+ T cells with distinct chemokine receptors in synovial fluid of patients with active rheumatoid arthritis. Scand. J. Rheumatol. 36, 428–433 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Shi, K. et al. Lymphoid chemokine B cell-attracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J. Immunol. 166, 650–655 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Pablos, J. L. et al. Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis. J. Immunol. 170, 2147–2152 (2003).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Rheumatology, Institute of Medicine, University of Debrecen Faculty of Medicine, Nagyerdei Str 98, Debrecen, H-4004, Hungary

    Zoltán Szekanecz

  2. Department of Internal Medicine, Division of Rheumatology, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Alisa E. Koch

Authors
  1. Zoltán Szekanecz
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  2. Alisa E. Koch
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Both authors contributed to researching data and writing the article, and to reviewing and editing the manuscript before submission.

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Correspondence to Zoltán Szekanecz.

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Szekanecz, Z., Koch, A. Successes and failures of chemokine-pathway targeting in rheumatoid arthritis. Nat Rev Rheumatol 12, 5–13 (2016). https://doi.org/10.1038/nrrheum.2015.157

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