WAM Essentials, Inc.

Enzyme therapy of experimental glomerulonephritis

Emancipator S.N. and Lamm M.E.

Institute of Pathology, Case Western Reserve University Cleveland, Ohio 44106, U.S.A.

In: Current Therapy in Nephrology, 1989, pp 582 -  Vydavatel: Kluwer Academic publishers - (Cleveland)

80 KA

Glomerulonephritis (GN), resulting from the deposition or formation of immune complexes (IC) within glomeruli, is often progressive and represents a major public health problem worldwide (1). Although progress within the last decade has helped to elucidate the pathogenesis of GN, therapy remains limited. Several mechanisms and inflammatory mediators are capable of contributing to disease, apparently operative in different combinations in the various patterns of GN (2). Therapy directed at particular pathways is consequently restricted in scope and may be of limited potential.

 We reasoned that digestion of glomerular immune deposits by enzymes could, to the extent that such deposits elicit GN, ameliorate the signs of disease and perhaps retard progression. Our earlier studies showed that non-toxic doses of proteolytic enzymes could markedly decrease IC deposits in the glomerular capillaries or mesangium in passive serum sickness GN models induced by injection of preformed IC of bovine gamma globulin (BGG) and rabbit antibody to BGG (3). Mice or rats treated systemically with mixtures of chymopapain and subtilisin did not display the intense immunofluorescence deposits seen in animals given the same amounts of IC but treated with saline instead of enzymes. The distribution of fluorescence intensities of rabbit antibodies in treated animals was significantly shifted to negative or low-grade scores compared to saline treated subjects, and antigen deposits were also significantly attenuated. We also quantified glomerular IC in rats given complexes of BGG antigen and radioactive rabbit anti-BGG and found that glomeruli from enzyme-treated rats contained only half the radioactivity present in rats treated with saline.

 In the active serum sickness model, rats given targeted or untargeted enzyme therapy for 5 days had significantly less proteinuria than saline-treated controls, despite the fact that protein excretion prior to treatment (84.6 ± 11.9 mg/day) was not different among the groups (F = 1.3). Rats given the naturally cationic avidin, which binds electrostatically to glomerular capillaries, and then given biotinyl protease capable of binding tightly to the avidin, had significantly less proteinuria than rats given nontargeted proteases, either biotinyl protease alone or unmodified protease plus avidin. Moreover, rats given protease targeted to glomerular capillaries by avidin and biotin had the least intense glomerular deposits by immunofluorescence of all the groups (data not shown). The benefits of protease therapy are additionally evident in their amelioration of the hypercholesterolemia associated with the nephrotic syndrome in these rats (normal rat serum cholesterol is 98 ± 4.2 mg/dl). Again, targeted protease was significantly better than nontargeted protease.