Prevention of renal damage in murine lupus nephritis by CTLA-4Ig and cyclophosphamide

Abstract

Objective To compare the effects of combined administration of cyclophosphamide (CYC) and CTLA-4Ig with the effects of these agents alone on the immunopathology and progression of renal damage in (NZB × NZW)F₁ (B/W) lupus-prone mice, and to explore the clinical implications of this combination by evaluating the ability of CTLA-4Ig to sustain the benefit of CYC in patients with lupus nephritis. Methods We carried out a detailed, prospective pathologic and immunohistochemical analysis of the effects of CYC and CTLA-4Ig, alone and in combination, in kidney tissue from B/W mice. The acute effects of these agents on immune cells in the kidney were evaluated by fluorescence-activated cell sorting. We also compared the effect of brief CYC plus sustained CTLA-4Ig administration with the effect of sustained administration of both agents on the progression of renal disease in B/W mice. Results As a single agent, CTLA-4Ig was generally as effective, and in some cases more effective, than CYC in slowing progression of renal disease. Combined therapy with these two agents very effectively arrested the progression of renal damage and, in some respects, reversed renal pathology. Induction therapy with both CTLA-4Ig and CYC precluded the need for continuous administration of CYC. Conclusion Our results indicate that the combination of CTLA-4Ig and CYC very effectively arrests the progression of murine lupus nephritis. These findings have direct implications for the treatment of lupus nephritis.