Effect of intravenous cyclophosphamide in systemic lupus erythematosus: relation to lymphocyte subsets and activation markers

Abstract

Since the mechanism mediating the beneficial effect of intravenous cyclophosphamide (IVCY) in systemic lupus erythematosus (SLE) is unknown, we investigated lymphocyte subsets and markers of activated lymphocytes in patients received IVCY, and compared the results with the effect of steroid pulse. In 55 patients with SLE, 34 patients receiving IVCY [21 cases (61.8%) were responsive] and 25 patients received steroid pulse [21 cases (84.0%) were responsive] (four patients who were resistant to steroid pulse therapy were transferred to IVCY). When the lymphocyte subsets and markers of activated lymphocytes were compared in the responsive and unresponsive group of IVCY, soluble CD4 levels and the ratio of HLA-DP-positive T cells were significantly higher in the unresponsive group. Further, the changes of these markers and costimulatory molecules [LFA-1 (CD11a), ICAM-1 (CD54), CD40 and CD40-ligand (CD154)] were also examined in the responsive patients. The ratio of HLA-DP-positive T cells did not change in the IVCY-responsive group, while it decreased in the steroid pulse therapy-responsive group. The ratio of CD11a on T cells increased and CD54 on B cells decreased in the IVCY-responsive group. The ratio of CD154 on T cells increased in the steroid pulse-responsive group, while it decreased in the IVCY-responsive group. These results suggest that the effect of IVCY is different to that of steroid pulse therapy and mainly related to B cell activation, and that these markers may contribute to predict the responsiveness of IVCY.

Keywords

activated lymphocytes costimulatory molecules intravenou scyclophosphamide systemic lupus erythematosus

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References

Wallace DJ , Podell T , Weiner DPG et al. Systemic lupus erythematosus-survival patterns: experience with 609 patients . JAMA 1981; 245: 934–938 .

Balow JE , Austin HA III , Meunz LR . Effect of treatment on the evolution of renal abnormalities in lupus nephritis . N Engl J Med 1984; 311: 491–495 .

Austin HA III , Klippel JH , Balow JE . Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs . N Engl J Med 1986; 314: 614–619 .

Felson DT , Anderson J . Evidence for the superiority of immunosuppressive drugs and prednisone over prednisone alone in lupus nephritis: results of a pooled analysis . N Engl J Med 1984; 311: 1528–1533 .

Dinant HJ , Decker JD , Klippel JH et al. Alternative modes of cyclophosphamide and azathioprine therapy in lupus nephritis . Ann Intern Med 1982; 96: 728–736 .

Plotz PH , Klippel JH , Decker JL . Bladder complications in patients receiving cyclophosphamide for systemic lupus erythematosus or rheumatoid arthritis . Ann Intern Med 1979; 91: 221–223 .

Boumpas DT , Austin HA III , Vaughn EM . Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis . Lancet 1992; 340: 741–745 .

Neuwelt CM , Lacks S , Kaye BR et al. Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus . Am J Med 1995; 98: 32–41 .

Walport MJ , Hubbard WN , Hughes GRV . Reversal of aplastic anemia secondary to systemic lupus erythematosus by high-dose intravenous cyclophosphamide . BMJ 1982; 285: 769–770 .

10.

Boumpas DT , Barez Shirin , Klippel JH , Balow James E . Intermittent cyclophosphamide for the treatment of autoimmune thrombocytopenia in systemic lupus erythematosus . Ann Intern Med 1990; 112: 674–677 .

11.

Eiser AR , Shanies HM . Treatment of lupus interstitial lung disease with intravenous cyclophosphamide . Arthritis Rheum 1994; 37: 428–431 .

12.

Cupps TR , Edgar LC , Fauci AS . Suppression of human B lymphocyte function by cyclophosphamide . J Immunol 1982; 128: 2453–2457 .

13.

Takeno M , Suzuki N , Nagafuchi H . Selective suppression of resting B cell function in patients with systemic lupus erythematosus treated with cyclophosphamide . Clin Exp Rheumatol 1993; 11: 263–270 .

14.

Ozer H Jr , Cowens JW , Colvin M et al. In vitro effects of 4 hydroperoxycyclophosphamide on human immunoregulatory T subset function . J Exp Med 1982; 155: 276–290 .

15.

Bast Jr RC , Rheinherz EL , Maver C et al. Contrasting effects of cyclophosphamide and prednisone on the phenotype of human peripheral blood leukocytes . Clin Immunol Imunopathol 1983; 28: 101–114 .

16.

Tan MT , Cohen AS , Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271–1277 .

17.

Claire B , Dafna DG , Murray BU et al. Derivation of the SLEDAI . Arthritis Rheum 1992; 35: 630–640 .

18.

Churg J , Bernstein J , Glassock RJ . Lupus nephritis in renal disease classification and atlas of glomerular diseases . Igaku-shoin Medical Publishers 1995; 151–156 .

19.

Hashimoto H , Sugawara M , Tsuda H et al. Studies on the outcome of lupus nephritis according to long-term treatment employing different modes of immunotherapy . Jpn J Nephrol 1992; 34: 1003–1009 .

20.

Inghirami G , Wieczorek R , Zhu BY et al. Differential expression of LFA-1 molecules in non-Hodgkin's lymphoma and lymphoid leukemia . Blood 1988; 72: 1431–1434 .

21.

Mentzer SJ , Faller DV , Burakoff SJ . Interferon-g induction of LFA-1-mediated homotypic adhesion of human monocytes . J Immunol 1986; 137: 108–113 .

22.

Clark EA , Ledbetter JA , Holly RC et al. Polypeptides on human B lymphocytes associated with cell activation . Hum Immunol 1986; 16: 100–113 .

23.

Fuleihan R , Ramesh N , Horner A . Cyclosporin A inhibits CD40 ligand expression in T lymphocytes . J Clin Invest 1994; 93: 1315-1315 .

24.

Galy AHM , Spits H . CD40 is functionally expressed on human thymic epithelial cells . J Immunol 1992; 149: 775-775 .

25.

Tokano Y , Hishikawa T , Hirose T et al. HLA-DP-positive T cells patient with systemic lupus erythematosus . Autoimmunity 1990; 5: 179–183 .

26.

Kanai Y , Takano Y , Tsuda H et al. HLA-DP positive T cells in patients with polymyositis/dermatomyositis . J Rheumatol 1993; 20: 77–79 .

27.

Hirose T , Goto M , Okumura K . HLA-DR, DQ and DP antigen expression in synovial fiuid T lymphocytes in rheumatoid arthritis: cell cycle analysis of HLA-DP positive T cells . J Rheumatol 1990; 17: 18–23 .

28.

Binnerts ME , Kooyk VY , Simmons DL , Figdor CG . Distinct binding of T lymphocytes to ICAM-1,-2 or-3 upon activation of LFA-1 . Eur J Immunol 1994; 24: 2155–2160 .

29.

Armitage RJ , Fanslow WC , Strockbine L , Spriggs MK . Molecular and biological characterization of a murine ligand for CD40 . Nature 1992; 357: 80–82 .

30.

Ellis JH , Burden MN , Vinogradov DV et al. Interactions of CD80 and CD86 with CD28 and CTLA-4 . J Immunol 1996; 156: 2700–2709 .

31.

Griggs ND , Agersborg SS , Noelle RJ , Ledbetter JA . The relative contribution of the CD28 and gp39 costimulatory pathways in the clonal expansion and pathogenic acquisition of self-reactive T cells . J Exp Med 1996; 183: 801–810 .

32.

Mehta Ad , Lu L , Goldman RR , Datta S . Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production . J Clin Invest 1996; 97: 2063–2073 .

33.

Shinde S , Wu Y , Guo Y , Niu Q . CD40L is important for induction of, but not response to, costimulatory activity . J Immunol 1996; 157: 2764–2768 .

34.

Nakajima A , Azuma M , Kodera S , Nuriya S . Preferential dependence of autoantibody production in murine lupus on CD86 co-stimulatory molecule . Eur J Immunol 1995; 25: 3060–3069 .

35.

Early GS , Zhao W , Burns CM . Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of NZB/NZW mice . J Immunol 1996; 157: 3159–3164 .

36.

Gourly MF , Austin III HA , Scott D et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis . Ann Intern Med 1996; 125: 549–557 .