Effects of anti-CD4 antibodies on the release of IL-6 and TNF-α in whole blood samples from patients with systemic lupus erythematosus

Abstract

Anti-CD4 antibodies have been recently introduced into the therapy of various autoimmune diseases, among them systemic lupus erythematosus (SLE). Their modes of action are not yet fully understood. Interference with cytokine release may be one possible mechanism. Therefore, the effects of anti-CD4 antibodies on the cytokine release of IL-6 (interleukin-6) and TNF-a (tumor necrosis factor alpha) were investigated in a whole blood culture system. Basal and phytohemagglutin/lipopolysaccharide (PHA/LPS)-stimulated cytokine patterns were compared to cytokine release after the addition of anti-CD4 antibodies (MAX. 166H5) or methylprednisolone in short time whole blood cell culture systems from 12 patients with active SLE, 23 patients with inactive SLE and 12 healthy volunteers. TNF-oc and IL-6 concentrations were determined in the supernatants by ELISA. High disease activity correlated with an increased production of proinflammatory cytokines. Cell cultures of patients with inactive SLE showed a diminished capacity to respond to mitogenic stimulation. Anti-CD4 antibodies added in vitro suppressed significantly the unstimulated production of IL-6 (P < 0.02) in the cell cultures of patients with active SLE and in the PHA/LPS-stimulated cell cultures from both groups of SLE patients (both P < 0.001) and healthy volunteers (P < 0.01). However, MAX.16H5 did not affect the release of TNF-a. In control samples methylprednisolone considerably reduced stimulated and unstimulated IL-6 and TNF-ca production in all SLE patients, irrespective of the disease state, and in all healthy controls.

These data indicate that the proinflammatory cytokines are involved in the pathogenesis of SLE. It is assumed that anti-CD4 antibodies, which can be effective in the treatment of highly active lupus patients, may act via their influence on cytokine release. The decrease of the proinflammatory cytokines IL-6 under therapy with MAX. 16H5 could explain the observations of clinical trials and animal studies which showed a reduction of inflammatory parameters and diminished production of autoantibodies following treatment with anti-CD4 antibodies.

Keywords

systemic lupus erythematosus anti-CD4 antibody MAX.16H5 interleukin-6 tumor necrosis factor-alpha

References

1 Shoenfeld Y , Isenberg D . DNA antibody idiotypes: a review of their genetic, clinical, and immunopathologic features . Semin Arthritis Rheum 1987; 16: 245-252 .

2 Handwerger BS , Rus V , da Silva L , Via CS . The role of cytokines in the immunopathogenesis of lupus . Semin Immunopathol 1994; 16: 153-180 .

3 Via CS , Handwerger BS . T-cell and B-cell function in lupus . Curr Opin Rheumatol 1992; 4: 630-630 .

4 Horwitz DA , Jacob CO . The cytokine network in the pathogenesis of systemic lupus erythematosus and possible therapeutic implications . Semin Immunopathol 1994; 16: 181-200 .

5 Spronk PE , ter Borg EJ , Limburg PC , Kallenberg CG . Plasma concentration of IL-6 in systemic lupus erythematosus; an indicator of disease activity? Clin Exp Immunol 1992; 90: 106-110 .

6 al-Janadi M , al-Balla S , al-Dalaan A , Raziuddin S . Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheu-matic diseases . J Clin Immunol 1993; 13: 58-67 .

7 Linker Israeli M . Cytokine abnormalities in human lupus . Clin Immunol Immunopathol 1972; 63: 10-12 .

8 Davas EM , Tsirogianni A , Kappou I . Serum IL-6, TNFalpha, p55 srTNFalpha, p75srTNFalpha, srIL-2alpha levels and disease activity in systemic lupus erythematosus . Clin Rheumatol 1999; 18: 17-22 .

9 Lacki JK , Samborski W , Mackiewicz SH . Interleukin-lO and interleukin-6 in lupus erythematosus and rheumatoid arthritis, correlations with acute phase proteins . Clin Rheumatol 1997; 16: 275-278 .

10.

10 Hirohata S , Miyamoto, T . Elevated levels of interleukin-6 in cerebrosp-inal fluid from patients with systemic lupus erythematosus and central nervous system involvement . Arthritis Rheum 1990; 33: 644-649 .

11.

11 Neng Lai K , Leung JC , Bik Lai K et al. Anti-DNA autoantibodies stimulate the release of interleukin-1 and interleukin-6 from endothe-lial cells . J Pathol 1996; 178: 451-457 .

12.

12 Morel P , Vincent C , Wijdenes J , Revillard JP . Down-regulation of cell surface CD4 molecule expression induced by anti-CD4 antibodies in human T lymphocytes . Cell Immunol 1992; 145: 287-298 .

13.

13 Wofsy D , Chiang NY , Greenspan JS , Ermak TH . Treatment of murine lupus with monoclonal antibody to L3T4. I. Effects on the distribution and function of lymphocyte subsets and on the histopathology of autoimmune disease . J Autoimmun 1988; 1: 415-431 .

14.

14 Wofsy D . Treatment of murine lupus with anti-CD4 monoclonl antibodies . Immunol Ser 1993; 59: 221-236 .

15.

15 Brink I. Treatment with monoclonal anti-CD4 antibodies in patients with severe systemic lupus erythematosus (German). Degree thesis, Humboldt-University, Berlin, 1995.

16.

16 Hiepe F , Volk HD , Apostolff E et al. Treatment of severe systemic lupus erythematosus with anti-CD4 monoclonal antibody . Lancet 1991; 338: 1529-1530 .

17.

17 Hiepe F , Brink I , Thiele B et al. Treatment of severe systemic lupus erythemtosus (SLE) with monoclonal anti-CD4 antibodies (MAX. 16H5) . Arthritis Rheum 1995; 38(Suppl.): S303-S303 (abstract).

18.

18 Kupiec-Weglinski JW , Wasowska B , Papp I et al. CD4 mAb therapy modulates alloantibody production and intracardiac graft deposition in association with selective inhibition of Thl lymphokines . J Immunol 1993; 151: 5053-5061 .

19.

19 Siegling A , Lehmann M , Riedel H et al. A nondepleting anti-rat CD4 monoclonal antibody that suppresses T helper 1-like but not T helper 2-like intragraft lymphokine secretion induces long-term survival of renal allografts . Transplantation 1994; 57: 464-467 .

20.

20 Horneff G , Sack U , Kalden JR et al. 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 . Clin Exp Immnunol 1993; 91: 207-213 .

21.

21 Tan EM , Cohen AS , Fries JI et al. The 1982 revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271-1277 .

22.

22 Guse AH , Mitton AD , Schulze-Koops H et al. Purification and analytical characterization of an anti-CD4 monoclonal antibody for human therapy . J Chromatogr A 1994; 661: 13-23 .

23.

23 Guse AH , Tsygankov AY , Broker BM et al. Signal Transduction in T lymphocytes and monocytes: effects of the anti-CD4 antibody MAX.16H5 . Yer Immunol 1993; 7: 175-181 .

24.

24 Burmester GR , Emmrich F . Anti-CD4 therapy in rheumatoid arthritis . Clin Exp Rheumatol 1993; 11 Suppl 8: S139-S145 .

25.

25 Horneff G , Burmester GR , Emmrich F , Kalden JR . Treatment of rheumatoid arthritis with an anti-CD4 monoclonal antibody . Arthritis Rheum 1991; 34: 129-140 .

26.

26 Horneff G , Dirksen U , Schulze-Koops H et al. Treatment of refractory juvenile chronic arthritis by monoclonal CD4 antibodies: a pilot study in two children . Ann Rheum Dis 1995; 54: 846-849 .

27.

27 Emmrich J , Seyfarth M , Fleig WE , Emmrich F . Treatment of inflammatory bowel disease with anti-CD4 monoclonal antibody . Lancet 1991 338: 570-571 .

28.

28 Boumpas DT , Chrousos GP , Wilder RL et al. Glucocortocoid therapy for immune-mediated diseases: basic and clinical correlates . Ann Intern Med 1993; 119: 1198-1208 .

29.

29 Buttgereit F , Brink I , Thiele B et al. Effects of methylprednisolone and 21-aminosteroids on mitogen-induced interleukin-6 and tumor necrosis factor-alpha production in human peripheral blood mononuclear cells . J PharmacolExp Ther 1995; 275: 850-853 .

30.

30 Bloemena E , Roos MT , Van HJ et al. Whole-blood lymphocyte cultures . J Immunol Methods 1989; 122: 161-167 .

31.

31 Swaak AJ , van den Brink HG , Aarden LA . Cytokine production (IL-6 and TNF alpha) in whole blood cell cultures of patients with systemic lupus erythematosus . Scand J Rheumatol 1996; 25: 233-238 .

32.

32 Linker Israeli M , Deans RJ , Wallace DJ et al. Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis . J Immunol 1991; 147: 117-123 .

33.

33 Horwitz DA . Mechanisms producing decreased mitogenic reactivity in patients with systemic lupus erythematosus and other rheumatic deceases. In: Oppenheim JJ , Rosenstreich DL (eds). Mitogens and immunobiology Academic Press: New York , 1976.

34.

34 Chu CQ , Field M , Feldmann M , Maini RN . Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis . Arthritis Rheum 1991; 34: 1125-1132 .

35.

35 Tetta C , Camussi G , Modena V et al. Tumour necrosis factor in serum and synovial fluid of patients with active and severe rheumatoid arthritis . Ann Rheum Dis 1990; 49: 665-667 .

36.

36 van der Lubbe PA , Dijkmans BA , Markusse HM et al. A randomized, double-blind, placebo-controlled study of CD4 monoclonal antibody therapy in early rheumatoid arthritis . Arthritis Rheum 1995; 38: 1097-1106 .

37.

37 Jacob CO , Hwang F , Lewis GD , Stall AM . Tumor necrosis factor alpha in murine systemic lupus erythematosus disease models: implications for genetic predisposition and immune regulation . Cytokine 1991; 3: 551-561 .

38.

38 Aderka D , Wysenbeek A , Englemann H et al. Correlation between serum levels of soluble tumor necrosis factor receptor and disease activity in systemic lupus erythematosus . Arthritis Rheum 1993; 36: 1111-1120 .

39.

39 Studnicka-Benke A , Steiner G , Petera P , Smolen JS . Tumour necrosis factor alpha and its soluble receptors parallel clinical disease and autoimmune activity in systemic lupus erythematosus . Br J Rheumatol 1996; 35: 1067-1074 .

40.

40 Kitani A , Hara M , Hirose T et al. Autostimulatory effects of IL-6 on excessive B cell differentiation in patients with systemic lupus erythematosus: analysis of IL-6 production and IL-6R expression . Clin Exp Immunol 1992; 88: 75-83 .

41.

41 Stewart SJ , Fujimoto J , Levy R . Human T lymphocytes and monocytes bear the same Leu-3(T4) antigen . J Immunol 1986; 136: 3773-3778 .

42.

42 Elliott MJ , Maini RN . New directions for biological therapy in rheumtoid arthritis . Int Arch Allergy Immunol 1994; 104: 112-125 .