Enzyme therapy of experimental glomerulonephritis
Steven N. Emancipator and Michael E. Lamm
Institute of Pathology, Case Western Reserve University Cleveland, Ohio 44106, U.S.A.
In: Current Therapy in Nephrology, V.E. Andreucci, A. Val Canton (eds.), Cleveland 1989, pp 582
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.
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