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. 1993 Feb;91(2):207–213. doi: 10.1111/j.1365-2249.1993.tb05884.x

Reduction of monocyte-macrophage activation markers upon anti-CD4 treatment. Decreased levels of IL-1, IL-6, neopterin and soluble CD14 in patients with rheumatoid arthritis.

G Horneff 1, U Sack 1, J R Kalden 1, F Emmrich 1, G R Burmester 1
PMCID: PMC1554673  PMID: 7679058

Abstract

Anti-CD4 MoAbs have been successfully used in initial treatment trials of rheumatoid arthritis. One remarkable feature of this therapy was the early reduction of synovitis along with a decrease of the erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP). Since not only T helper cells, but also monocytes-macrophages bear the CD4 antigen, the question was raised whether the immediate effects observed may have been in part due to an influence on the mononuclear phagocyte system. Immediately after MoAb infusions, a significant reduction of the absolute peripheral blood monocyte count down to 30% (P < 0.001) was noted within the first hour of injection. In contrast to strikingly elevated levels of soluble CD4 after treatment which was indicative of T cell lysis, soluble CD14 levels did not rise, but rather decreased from previously elevated levels. Before treatment, activation of the monocyte-macrophage system had been signified by elevated serum levels of IL-1, IL-6, CRP and neopterin as well as a marked in vitro production of IL-1, tumour necrosis factor-alpha (TNF-alpha) and IL-6. Subsequent anti-CD4 treatment resulted in a rapid and significant reduction of monocyte-derived circulating cytokines and mediators concordant with a reduced capacity to produce IL-1, TNF-alpha, and IL-6 in those patients who demonstrated clinical benefits. Therefore, studies of monocyte activation markers may be useful in identifying subsequent responders to anti-CD4 therapy.

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Selected References

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  1. Aarden L. A., De Groot E. R., Schaap O. L., Lansdorp P. M. Production of hybridoma growth factor by human monocytes. Eur J Immunol. 1987 Oct;17(10):1411–1416. doi: 10.1002/eji.1830171004. [DOI] [PubMed] [Google Scholar]
  2. Arend W. P., Dayer J. M. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990 Mar;33(3):305–315. doi: 10.1002/art.1780330302. [DOI] [PubMed] [Google Scholar]
  3. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  4. Bazil V., Horejsí V., Baudys M., Kristofová H., Strominger J. L., Kostka W., Hilgert I. Biochemical characterization of a soluble form of the 53-kDa monocyte surface antigen. Eur J Immunol. 1986 Dec;16(12):1583–1589. doi: 10.1002/eji.1830161218. [DOI] [PubMed] [Google Scholar]
  5. Biddison W. E., Rao P. E., Talle M. A., Goldstein G., Shaw S. Possible involvement of the OKT4 molecule in T cell recognition of class II HLA antigens. Evidence from studies of cytotoxic T lymphocytes specific for SB antigens. J Exp Med. 1982 Oct 1;156(4):1065–1076. doi: 10.1084/jem.156.4.1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Burmester G. R., Dimitriu-Bona A., Waters S. J., Winchester R. J. Identification of three major synovial lining cell populations by monoclonal antibodies directed to Ia antigens and antigens associated with monocytes/macrophages and fibroblasts. Scand J Immunol. 1983 Jan;17(1):69–82. doi: 10.1111/j.1365-3083.1983.tb00767.x. [DOI] [PubMed] [Google Scholar]
  7. Burmester G. R., Jahn B., Rohwer P., Zacher J., Winchester R. J., Kalden J. R. Differential expression of Ia antigens by rheumatoid synovial lining cells. J Clin Invest. 1987 Sep;80(3):595–604. doi: 10.1172/JCI113111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Burmester G. R., Kalden J. R., Peter H. H., Schedel I., Beck P., Wittenborg A. Immunological and functional characteristics of peripheral blood and synovial fluid lymphocytes from patients with rheumatoid arthritis. Scand J Immunol. 1978;7(5):405–417. doi: 10.1111/j.1365-3083.1978.tb00471.x. [DOI] [PubMed] [Google Scholar]
  9. Burmester G. R., Yu D. T., Irani A. M., Kunkel H. G., Winchester R. J. Ia+ T cells in synovial fluid and tissues of patients with rheumatoid arthritis. Arthritis Rheum. 1981 Nov;24(11):1370–1376. doi: 10.1002/art.1780241106. [DOI] [PubMed] [Google Scholar]
  10. Chin J. E., Winterrowd G. E., Krzesicki R. F., Sanders M. E. Role of cytokines in inflammatory synovitis. The coordinate regulation of intercellular adhesion molecule 1 and HLA class I and class II antigens in rheumatoid synovial fibroblasts. Arthritis Rheum. 1990 Dec;33(12):1776–1786. doi: 10.1002/art.1780331204. [DOI] [PubMed] [Google Scholar]
  11. Dimitriu-Bona A., Burmester G. R., Waters S. J., Winchester R. J. Human mononuclear phagocyte differentiation antigens. I. Patterns of antigenic expression on the surface of human monocytes and macrophages defined by monoclonal antibodies. J Immunol. 1983 Jan;130(1):145–152. [PubMed] [Google Scholar]
  12. Gauldie J., Richards C., Harnish D., Lansdorp P., Baumann H. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7251–7255. doi: 10.1073/pnas.84.20.7251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Henderson D. C., Sheldon J., Riches P., Hobbs J. R. Cytokine induction of neopterin production. Clin Exp Immunol. 1991 Mar;83(3):479–482. doi: 10.1111/j.1365-2249.1991.tb05664.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Herzog C., Walker C., Pichler W., Aeschlimann A., Wassmer P., Stockinger H., Knapp W., Rieber P., Müller W. Monoclonal anti-CD4 in arthritis. Lancet. 1987 Dec 19;2(8573):1461–1462. doi: 10.1016/s0140-6736(87)91158-5. [DOI] [PubMed] [Google Scholar]
  15. Horneff G., Burmester G. R., Emmrich F., Kalden J. R. Treatment of rheumatoid arthritis with an anti-CD4 monoclonal antibody. Arthritis Rheum. 1991 Feb;34(2):129–140. doi: 10.1002/art.1780340202. [DOI] [PubMed] [Google Scholar]
  16. Huber C., Batchelor J. R., Fuchs D., Hausen A., Lang A., Niederwieser D., Reibnegger G., Swetly P., Troppmair J., Wachter H. Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma. J Exp Med. 1984 Jul 1;160(1):310–316. doi: 10.1084/jem.160.1.310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Janossy G., Panayi G., Duke O., Bofill M., Poulter L. W., Goldstein G. Rheumatoid arthritis: a disease of T-lymphocyte/macrophage immunoregulation. Lancet. 1981 Oct 17;2(8251):839–842. doi: 10.1016/s0140-6736(81)91107-7. [DOI] [PubMed] [Google Scholar]
  18. Krüger C., Schütt C., Obertacke U., Joka T., Müller F. E., Knöller J., Köller M., König W., Schönfeld W. Serum CD14 levels in polytraumatized and severely burned patients. Clin Exp Immunol. 1991 Aug;85(2):297–301. doi: 10.1111/j.1365-2249.1991.tb05722.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kupper T., Horowitz M., Lee F., Robb R., Flood P. M. Autocrine growth of T cells independent of interleukin 2: identification of interleukin 4 (IL 4, BSF-1) as an autocrine growth factor for a cloned antigen-specific helper T cell. J Immunol. 1987 Jun 15;138(12):4280–4287. [PubMed] [Google Scholar]
  20. Lipsky P. E., Davis L. S., Cush J. J., Oppenheimer-Marks N. The role of cytokines in the pathogenesis of rheumatoid arthritis. Springer Semin Immunopathol. 1989;11(2):123–162. doi: 10.1007/BF00197186. [DOI] [PubMed] [Google Scholar]
  21. MacNaul K. L., Hutchinson N. I., Parsons J. N., Bayne E. K., Tocci M. J. Analysis of IL-1 and TNF-alpha gene expression in human rheumatoid synoviocytes and normal monocytes by in situ hybridization. J Immunol. 1990 Dec 15;145(12):4154–4166. [PubMed] [Google Scholar]
  22. Reibnegger G., Egg D., Fuchs D., Günther R., Hausen A., Werner E. R., Wachter H. Urinary neopterin reflects clinical activity in patients with rheumatoid arthritis. Arthritis Rheum. 1986 Sep;29(9):1063–1070. doi: 10.1002/art.1780290902. [DOI] [PubMed] [Google Scholar]
  23. Reiter C., Kakavand B., Rieber E. P., Schattenkirchner M., Riethmüller G., Krüger K. Treatment of rheumatoid arthritis with monoclonal CD4 antibody M-T151. Clinical results and immunopharmacologic effects in an open study, including repeated administration. Arthritis Rheum. 1991 May;34(5):525–536. doi: 10.1002/art.1780340504. [DOI] [PubMed] [Google Scholar]
  24. Schütt C., Ringel B., Nausch M., Bazil V., Horejsí V., Neels P., Walzel H., Jonas L., Siegl E., Friemel H. Human monocyte activation induced by an anti-CD14 monoclonal antibody. Immunol Lett. 1988 Dec;19(4):321–327. doi: 10.1016/0165-2478(88)90162-9. [DOI] [PubMed] [Google Scholar]
  25. Seitz M., Napierski I., Augustin R., Hunstein W., Kirchner H. Reduced production of interferon alpha and interferon gamma in leukocyte cultures from patients with active rheumatoid arthritis. Scand J Rheumatol. 1987;16(4):257–262. doi: 10.3109/03009748709102926. [DOI] [PubMed] [Google Scholar]
  26. Smith M. D., Ahern M. J., Brooks P. M., Roberts-Thomson P. J. The clinical and immunological effects of pulse methylprednisolone therapy in rheumatoid arthritis. II. Effects on immune and inflammatory indices in peripheral blood. J Rheumatol. 1988 Feb;15(2):233–237. [PubMed] [Google Scholar]
  27. Walther Z., May L. T., Sehgal P. B. Transcriptional regulation of the interferon-beta 2/B cell differentiation factor BSF-2/hepatocyte-stimulating factor gene in human fibroblasts by other cytokines. J Immunol. 1988 Feb 1;140(3):974–977. [PubMed] [Google Scholar]
  28. Wendling D., Wijdenes J., Racadot E., Morel-Fourrier B. Therapeutic use of monoclonal anti-CD4 antibody in rheumatoid arthritis. J Rheumatol. 1991 Mar;18(3):325–327. [PubMed] [Google Scholar]
  29. Wright S. D., Ramos R. A., Tobias P. S., Ulevitch R. J., Mathison J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990 Sep 21;249(4975):1431–1433. doi: 10.1126/science.1698311. [DOI] [PubMed] [Google Scholar]

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