In rats with the proliferative
immune complex glomerulonephritis of chronic
serum sickness, kidney function deteriorates in three discrete and readily distinguishable stages: Mild, Moderate, and Severe. The mononuclear cell composition of glomerular
inflammation is also different in each stage. The immunosuppressive
drug,
cyclosporin A, was administered to rats with chronic
serum sickness in order to investigate the relationship between glomerular immunopathology and pathophysiology in proliferative
immune complex nephritis. When introduced after the onset of
proteinuria, daily treatment with
cyclosporin A failed to prevent the progression from Moderate to Severe
nephritis, which is characterized by the abnormal differentiation and local proliferation of glomerular macrophages, as well as grave deterioration in kidney function. In contrast, when
cyclosporin A therapy started before the onset of
proteinuria, the course of proliferative
glomerulonephritis was altered significantly. Although the levels of
proteinuria and macrophage accumulation that are characteristic of the Moderate stage of
nephritis were not reduced, progression to Severe
nephritis did not occur. The number of glomerular macrophages appeared to increase in two separate phases in this chronic
serum sickness model of proliferative
immune complex glomerulonephritis. The first phase, which coincided with the onset of
proteinuria, did not require T cells and culminated only in moderate hypercellularity and
proteinuria. The second increase in the number of glomerular macrophages, which was accompanied by the expression of abnormal macrophage phenotypes, was closely linked to the development of severe
kidney insufficiency. The protective effect of
cyclosporin A therapy was consistent with, although not conclusive proof for, the hypothesis that local T cell activation may contribute to the progression of proliferative
immune complex glomerulonephritis. Since
cyclosporin A can also directly influence the responses of macrophages and mesangial cells, the effect of the
drug on the course of
nephritis in this model might not be related to its immunosuppressive action.