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* Autoimmunity Center, Feinstein Institute for Medical Research, Manhasset, NY 11030;
Department of Medicine, Temple University, Philadelphia, PA 19104; and
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029
Costimulatory blockade with CTLA4Ig and anti-CD40L along with a single dose of cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice. To understand the mechanisms for remission and for impending relapse, we examined the expression profiles of 61 inflammatory molecules in the perfused kidneys of treated mice and untreated mice at different stages of disease. Further studies using flow cytometry and immunohistochemistry allowed us to determine the cellular origins of several key markers. We show that only a limited set of inflammatory mediators is expressed in the kidney following glomerular immune complex deposition but before the onset of proteinuria. Formation of a lymphoid aggregate in the renal pelvis precedes the invasion of the kidney by inflammatory cells. Regulatory molecules are expressed early in the disease process and during remission but do not prevent the inevitable progression of active inflammation. Onset of proliferative glomerulonephritis and proteinuria is associated with activation of the renal endothelium, expression of chemokines that mediate glomerular cell infiltration, and infiltration by activated dendritic cells and macrophages that migrate to different topographical areas of the kidney but express a similar profile of inflammatory cytokines. Increasing interstitial infiltration by macrophages and progressive tubular damage, manifested by production of lipocalin-2, occur later in the disease process. Studies of treated mice identify a type II (M2b)-activated macrophage as a marker of remission induction and impending relapse and suggest that therapy for systemic lupus erythematosus nephritis should include strategies that prevent both activation of monocytes and their migration to the kidney.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Lupus Research Institute (to A.D.), the Alliance for Lupus Research (to A.D.), the New York Systemic Lupus Erythematosus Foundation (to L.S., R.B., and M.R.), and National Institute of Allergy and Infectious Diseases.
2 Current address: Department of Nephrology, Hannover Medical School, Carl-Neuberg-Strasse 1OE 6840, Hannover, Germany.
3 R.B. and M.R. contributed equally to this work.
4 Address correspondence and reprint requests to Dr. Anne Davidson, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030. E-mail address: adavidson1{at}nshs.edu
5 Abbreviations used in this paper: SLE, systemic lupus erythematosus; qPCR, quantitative PCR; SAM, statistical analysis of microarray.
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