• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of annrheumdAnnals of the Rheumatic DiseasesCurrent TOCInstructions for authors
Ann Rheum Dis. Aug 2003; 62(8): 715–721.
PMCID: PMC1754636

Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis

Abstract

Background: Chemokines and their receptors are considered important contributors in cell migration and inflammation in chronic inflammatory disorders. Chemokines affecting monocytes/macrophages are considered potential therapeutic targets, but no studies of the effects of blocking the chemokine repertoire in humans with a chronic inflammatory disease have been reported.

Objective: To carry out a double blind, placebo controlled, phase Ib clinical trial with a specific, oral CCR1 antagonist.

Methods: 16 patients with active rheumatoid arthritis (RA) were randomised 3:1 to active:placebo treatment for 14 days. Synovial biopsy specimens were obtained on days 1 and 15. Immunohistochemistry was used to detect the presence of various cell types before and after treatment and the results measured by digital image analysis. Results before and after treatment were compared by paired t test, and a two sample t test was used to compare the changes from baseline in the two groups.

Results: All patients completed the study. A significant reduction in the number of macrophages (p=0.016), intimal macrophages (p=0.026), and CCR1+cells (p=0.049) in patients treated with the chemokine antagonist compared with the placebo group occurred in the synovium. Significant decreases in overall cellularity, intimal lining layer cellularity, CD4+ T cells, and CD8+ T cells also occurred in treated patients. Cells lacking CCR1 were not affected. Trends towards clinical improvement were seen in the treated patients but not in the placebo group. Severe side effects were not reported.

Conclusion: Specific chemokine receptor blockade can result in relevant biological effects in patients with active RA.

Full Text

The Full Text of this article is available as a PDF (352K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001 Sep 15;358(9285):903–911. [PubMed]
  • Kremer JM. Methotrexate and radiographic disease progression in patients with rheumatoid arthritis. J Rheumatol. 1999 Feb;26(2):241–243. [PubMed]
  • Cohen S, Cannon GW, Schiff M, Weaver A, Fox R, Olsen N, Furst D, Sharp J, Moreland L, Caldwell J, et al. Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Arthritis Rheum. 2001 Sep;44(9):1984–1992. [PubMed]
  • Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol. 2001;19:163–196. [PubMed]
  • Volin MV, Shah MR, Tokuhira M, Haines GK, Woods JM, Koch AE. RANTES expression and contribution to monocyte chemotaxis in arthritis. Clin Immunol Immunopathol. 1998 Oct;89(1):44–53. [PubMed]
  • Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, Pope RM, Strieter RM. Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest. 1994 Mar;93(3):921–928. [PMC free article] [PubMed]
  • Nanki T, Nagasaka K, Hayashida K, Saita Y, Miyasaka N. Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Immunol. 2001 Nov 1;167(9):5381–5385. [PubMed]
  • Conlon K, Lloyd A, Chattopadhyay U, Lukacs N, Kunkel S, Schall T, Taub D, Morimoto C, Osborne J, Oppenheim J, et al. CD8+ and CD45RA+ human peripheral blood lymphocytes are potent sources of macrophage inflammatory protein 1 alpha, interleukin-8 and RANTES. Eur J Immunol. 1995 Mar;25(3):751–756. [PubMed]
  • Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000 Feb;12(2):121–127. [PubMed]
  • Premack BA, Schall TJ. Chemokine receptors: gateways to inflammation and infection. Nat Med. 1996 Nov;2(11):1174–1178. [PubMed]
  • Katschke KJ, Jr, Rottman JB, Ruth JH, Qin S, Wu L, LaRosa G, Ponath P, Park CC, Pope RM, Koch AE. Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum. 2001 May;44(5):1022–1032. [PubMed]
  • al-Mughales J, Blyth TH, Hunter JA, Wilkinson PC. The chemoattractant activity of rheumatoid synovial fluid for human lymphocytes is due to multiple cytokines. Clin Exp Immunol. 1996 Nov;106(2):230–236. [PMC free article] [PubMed]
  • Robinson E, Keystone EC, Schall TJ, Gillett N, Fish EN. Chemokine expression in rheumatoid arthritis (RA): evidence of RANTES and macrophage inflammatory protein (MIP)-1 beta production by synovial T cells. Clin Exp Immunol. 1995 Sep;101(3):398–407. [PMC free article] [PubMed]
  • Barnes DA, Tse J, Kaufhold M, Owen M, Hesselgesser J, Strieter R, Horuk R, Perez HD. Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J Clin Invest. 1998 Jun 15;101(12):2910–2919. [PMC free article] [PubMed]
  • Plater-Zyberk C, Hoogewerf AJ, Proudfoot AE, Power CA, Wells TN. Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol Lett. 1997 Jun 1;57(1-3):117–120. [PubMed]
  • Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. [PubMed]
  • Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum. 1992 May;35(5):498–502. [PubMed]
  • Kraan MC, Reece RJ, Barg EC, Smeets TJ, Farnell J, Rosenburg R, Veale DJ, Breedveld FC, Emery P, Tak PP. Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers. Arthritis Rheum. 2000 Aug;43(8):1820–1830. [PubMed]
  • Tak PP, van der Lubbe PA, Cauli A, Daha MR, Smeets TJ, Kluin PM, Meinders AE, Yanni G, Panayi GS, Breedveld FC. Reduction of synovial inflammation after anti-CD4 monoclonal antibody treatment in early rheumatoid arthritis. Arthritis Rheum. 1995 Oct;38(10):1457–1465. [PubMed]
  • Kraan MC, Haringman JJ, Ahern MJ, Breedveld FC, Smith MD, Tak PP. Quantification of the cell infiltrate in synovial tissue by digital image analysis. Rheumatology (Oxford) 2000 Jan;39(1):43–49. [PubMed]
  • van Riel PL, van Gestel AM. Clinical outcome measures in rheumatoid arthritis. Ann Rheum Dis. 2000 Nov;59 (Suppl 1):i28–i31. [PMC free article] [PubMed]
  • Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Lightfoot R, Jr, Paulus H, Strand V, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995 Jun;38(6):727–735. [PubMed]
  • Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, Nuki G, Pavelka K, Rau R, Rozman B, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998 Dec;41(12):2196–2204. [PubMed]
  • Luster AD. Chemokines--chemotactic cytokines that mediate inflammation. N Engl J Med. 1998 Feb 12;338(7):436–445. [PubMed]
  • Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. [PubMed]
  • Baggiolini M. Chemokines in pathology and medicine. J Intern Med. 2001 Aug;250(2):91–104. [PubMed]
  • Kraan MC, Patel DD, Haringman JJ, Smith MD, Weedon H, Ahern MJ, Breedveld FC, Tak PP. The development of clinical signs of rheumatoid synovial inflammation is associated with increased synthesis of the chemokine CXCL8 (interleukin-8). Arthritis Res. 2001;3(1):65–71. [PMC free article] [PubMed]
  • Katrib A, Tak PP, Bertouch JV, Cuello C, McNeil HP, Smeets TJ, Kraan MC, Youssef PP. Expression of chemokines and matrix metalloproteinases in early rheumatoid arthritis. Rheumatology (Oxford) 2001 Sep;40(9):988–994. [PubMed]
  • Neote K, DiGregorio D, Mak JY, Horuk R, Schall TJ. Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor. Cell. 1993 Feb 12;72(3):415–425. [PubMed]
  • Rottman JB, Slavin AJ, Silva R, Weiner HL, Gerard CG, Hancock WW. Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur J Immunol. 2000 Aug;30(8):2372–2377. [PubMed]
  • Strieter RM, Standiford TJ, Huffnagle GB, Colletti LM, Lukacs NW, Kunkel SL. "The good, the bad, and the ugly." The role of chemokines in models of human disease. J Immunol. 1996 May 15;156(10):3583–3586. [PubMed]
  • Smeets TJ, Kraan MC, Versendaal J, Breedveld FC, Tak PP. Analysis of serial synovial biopsies in patients with rheumatoid arthritis: description of a control group without clinical improvement after treatment with interleukin 10 or placebo. J Rheumatol. 1999 Oct;26(10):2089–2093. [PubMed]
  • Cunnane G, Madigan A, Murphy E, FitzGerald O, Bresnihan B. The effects of treatment with interleukin-1 receptor antagonist on the inflamed synovial membrane in rheumatoid arthritis. Rheumatology (Oxford) 2001 Jan;40(1):62–69. [PubMed]
  • Youssef PP, Smeets TJ, Bresnihan B, Cunnane G, Fitzgerald O, Breedveld F, Tak PP. Microscopic measurement of cellular infiltration in the rheumatoid arthritis synovial membrane: a comparison of semiquantitative and quantitative analysis. Br J Rheumatol. 1998 Sep;37(9):1003–1007. [PubMed]

Figures and Tables

Figure 1
Significant decrease after CCR1 blockade therapy compared with placebo in the mean number (SEM) of (A) overall CD68+ cells (p=0.016), (B) intimal lining CD68+cells (p=0.026), and (C) CCR1+ cells (p=0.049) for the CCR1 antagonist group and the placebo ...
Figure 2
Expression of overall CD68+ cells (A), CD68+ lining cells (B), and CCR1+ cells (C) in paired synovial biopsy specimens after CCR1 blockade or placebo for the individual patients.
Figure 3
Representative synovial expression of CD68+ macrophages before and after treatment for a placebo patient (A, B) and a treated patient (C, D). Original magnification x400.
Figure 4
Representative synovial expression of CD4+ lymphocytes before and after treatment for a placebo patient (A, B) and a treated patient (C, D). Original magnification x400.
Figure 5
Representative synovial expression of CCR1+ cells before and after treatment for a placebo patient (A, B) and a treated patient (C, D). Original magnification x400.
Figure 6
Isotype-specific negative control. Original magnification x200.

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Group

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...