Nephrol Dial Transplant (1996) 11: 599-607
© 1996 European Renal Association-European Dialysis and Transplant Association
research-article
Different mediator systems in biphasic heterologous phase of anti-GBM nephritis in mice
Departments of Pathology, University Hospital Nijmegen Nijmegen, The Netherlands 1Dermatology and Internal Medicine, University Hospital Nijmegen Nijmegen, The Netherlands 2Division of Nephrology, University Hospital Nijmegen Nijmegen, The Netherlands
Correspondence and offprint requests to: Correspondence and offprint requests to: R. A. P. Koene, Department of Nephrology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands
BACKGROUND.: After the injection of rabbit anti-mouse glomerular basement membrane (GBM) antibody into normal C57BL/6J mice severe albuminuria develops, which reaches a peak at 24 h. This early albuminuria is dependent on polymorphonuclear granulocytes (PMN) and is completely absent in the congenic beige mutant strain (C57BL/6J, bg/bg), which is genetically deficient in leukocytic neutral proteinase activity. We now studied the development of anti-GBM nephritis in beige mice during the later heterologous phase.
METHODS.: In untreated beige mice we assessed the albuminuria and glomerular lesions on days 1–5 after i.v. injection of anti-GBM antibody. Secondly, effector mechanisms involved in the later days of the heterologous phase were studied by substitution of whole anti-GBM antibodies by F(ab')2 fragments, by leukocyte depletion (total body irradiation), scavenging of reactive oxygen metabolites (dimethylsulfoxide treatment), and complement depletion (cobra venom factor treatment).
RESULTS.: In the later part of the heterologous phase (days 2–5), when there is still no sign of autologous antibody formation, i.v. injection of anti-GBM anti-bodies in beige mice induces nephritis with gradually increasing albuminuria, that reaches levels similar to those in non-deficient, congenic controls by day 3. This late albuminuria did not occur after injection of F(ab')2 fragments of the antibody, could be prevented by leukocyte depletion, and was greatly reduced by treatment with dimethylsulfoxide, a scavenger of hydroxyl radicals. The late albuminuria was not influenced by complement depletion with cobra venom factor. Histologic and immunohistologic studies gave no indication for a role of glomerular macrophages or lymphocytes.
CONCLUSIONS.: The heterologous phase in murine anti-GBM nephritis is a biphasic process, with sequential involvement of different and independent mediating systems: both phases are PMN-dependent, but only the early albuminuria depends on leukocytic neutral proteinase activity, whereas the albuminuria and the glomerular damage at later days are effected by reactive oxygen metabolites, most probably originating from PMN accumulating in the glomerulus.
Keywords: albuminuria; anti-GBM nephritis; mice; monocytes; neutrophils
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