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Article

Hui Y. Lan^*, Michael Bacher, Niansheng Yang^*, Wei Mu^*, David J. Nikolic-Paterson^*, Christine Metz, Andreas Meinhardt, Richard Bucala, and Robert C. Atkins^*

From the ^* Department of Nephrology and the Institute for Reproduction and Development, Monash Medical Centre, Clayton, Victoria 3168, Australia; Picower Institute for Medical Research, Manhasset, New York 11030

Macrophage migration inhibitory factor (MIF) plays a pivotal role in the inflammatory response in endotoxemia and in the delayed-type hypersensitivity response, but its potential as a regulator of immunologically induced disease is unknown. We have addressed this issue by administering a neutralizing anti-MIF antibody in a rat model of immunologically induced crescentic anti-glomerular basement membrane (GBM) glomerulonephritis. Six individual experiments using paired inbred littermates were performed. Rats were primed with rabbit immunoglobulin on day –5 and then injection with rabbit anti–rat GBM serum on day 0. Pairs of animals were treated with anti-MIF or a control monoclonal antibody from the time of anti-GBM serum administration until being killed 14 d later. Control antibody-treated animals developed severe proteinuria and renal function impairment with severe histological damage due to marked leukocytic infiltration and activation within the kidney. In contrast, anti-MIF treatment substantially reduced proteinuria, prevented the loss of renal function, significantly reduced histological damage including glomerular crescent formation, and substantially inhibited renal leukocytic infiltration and activation (all P <0.001 compared with control treatment). Inhibition of renal disease by anti-MIF treatment was attributed to preventing the marked upregulation of interleukin-1β, leukocyte adhesion molecules including intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and inducible nitric oxide synthase expression seen in the control antibody-treated animals. This inhibition of progressive renal injury was mirrored by the complete suppression of the skin delayed-type hypersensitivity response to the challenge antigen (rabbit IgG). Interestingly, anti-MIF treatment did not effect the secondary antibody response or immune deposition within the kidney, indicating that MIF participates in cellular-based immunity in this primed macrophage-dependent anti-GBM glomerulonephritis. In conclusion, this study has demonstrated a key regulatory role for MIF in the pathogenesis of immunologically induced kidney disease. These results argue that blocking MIF activity may be of benefit in the treatment of human rapidly progressive glomerulonephritis, and suggest that MIF may be important in immune-mediated disease generally.

¹Abbreviations used in this paper: APAAP, alkaline phosphatase anti-alkaline phosphatase; DIG, digoxigenin; DTH, delayed-type hypersensitivity; GBM, glomerular basement membrane: GCS, glomerular cross-section; H&E, hematoxylin and eosin; ICAM, intercellular adhesion molecule; iNOS, inducible nitric oxide synthase; MIF, macrophage migration inhibitory factor; PAP, peroxidase anti-peroxidase; PAS, periodic acid– Schiff reagent; PLP, paraformaldehyde–lysine–periodate

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