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The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat.

Lan HY, Bacher M, Yang N, Mu W, Nikolic-Paterson DJ, Metz C, Meinhardt A, Bucala R, Atkins RC - J. Exp. Med. (1997)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.

ABSTRACT
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-1beta, 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.

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Effect of anti-MIF treatment on renal function in rat antiGBM disease. The effect of anti-MIF (open circles; dotted line) and irrelevant  control (closed circles; solid line) antibody treatment on the following: (a)  urinary protein excretion, (b) serum urea levels, (c) serum creatinine levels, and (d) creatinine clearance, was assessed at different times after injection of anti-GBM serum. Data is as the mean ± SEM for six animals. **P  <0.01, ***P <0.001 versus time-matched control antibody-treated animals, and; aP <0.05, bP <0.01, cP <0.001 versus normal rats (day 0) by  an unpaired two-sided Student's t-test.
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Figure 1: Effect of anti-MIF treatment on renal function in rat antiGBM disease. The effect of anti-MIF (open circles; dotted line) and irrelevant control (closed circles; solid line) antibody treatment on the following: (a) urinary protein excretion, (b) serum urea levels, (c) serum creatinine levels, and (d) creatinine clearance, was assessed at different times after injection of anti-GBM serum. Data is as the mean ± SEM for six animals. **P <0.01, ***P <0.001 versus time-matched control antibody-treated animals, and; aP <0.05, bP <0.01, cP <0.001 versus normal rats (day 0) by an unpaired two-sided Student's t-test.

Mentions: The induction of accelerated anti-GBM disease in rats treated with an irrelevant control mAb resulted in the development of severe proteinuria and a significant loss of renal function as assessed by increased levels of serum creatinine and urea and a reduction in the glomerular filtration rate indicated by creatinine clearance (Fig. 1). Although anti-MIF mAb treatment did not affect the induction of mild proteinuria on day 1, it did prevent the development of severe proteinuria over days 1–14 (Fig. 1 a). Importantly, normal renal function was maintained throughout the experimental period in anti-MIF mAb treated animals. In addition, anti-MIF treatment had no effect upon circulating white blood cell numbers (data not shown).


The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat.

Lan HY, Bacher M, Yang N, Mu W, Nikolic-Paterson DJ, Metz C, Meinhardt A, Bucala R, Atkins RC - J. Exp. Med. (1997)

Effect of anti-MIF treatment on renal function in rat antiGBM disease. The effect of anti-MIF (open circles; dotted line) and irrelevant  control (closed circles; solid line) antibody treatment on the following: (a)  urinary protein excretion, (b) serum urea levels, (c) serum creatinine levels, and (d) creatinine clearance, was assessed at different times after injection of anti-GBM serum. Data is as the mean ± SEM for six animals. **P  <0.01, ***P <0.001 versus time-matched control antibody-treated animals, and; aP <0.05, bP <0.01, cP <0.001 versus normal rats (day 0) by  an unpaired two-sided Student's t-test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196273&req=5

Figure 1: Effect of anti-MIF treatment on renal function in rat antiGBM disease. The effect of anti-MIF (open circles; dotted line) and irrelevant control (closed circles; solid line) antibody treatment on the following: (a) urinary protein excretion, (b) serum urea levels, (c) serum creatinine levels, and (d) creatinine clearance, was assessed at different times after injection of anti-GBM serum. Data is as the mean ± SEM for six animals. **P <0.01, ***P <0.001 versus time-matched control antibody-treated animals, and; aP <0.05, bP <0.01, cP <0.001 versus normal rats (day 0) by an unpaired two-sided Student's t-test.
Mentions: The induction of accelerated anti-GBM disease in rats treated with an irrelevant control mAb resulted in the development of severe proteinuria and a significant loss of renal function as assessed by increased levels of serum creatinine and urea and a reduction in the glomerular filtration rate indicated by creatinine clearance (Fig. 1). Although anti-MIF mAb treatment did not affect the induction of mild proteinuria on day 1, it did prevent the development of severe proteinuria over days 1–14 (Fig. 1 a). Importantly, normal renal function was maintained throughout the experimental period in anti-MIF mAb treated animals. In addition, anti-MIF treatment had no effect upon circulating white blood cell numbers (data not shown).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.

ABSTRACT
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-1beta, 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.

Show MeSH
Related in: MedlinePlus