GLOMERULONEPHRITIS INDUCED IN SHEEP BY INJECTIONS OF HETEROLOGOUS GLOMERULAR BASEMENT MEMBRANE AND FREUND'S COMPLETE ADJUVANT

Abstract

Sheep injected every 2 weeks with heterologous GBM and Freund's adjuvant by any one or combination of the following routes: intramuscular, subcutaneous, or intradermal, develop uniformly a fulminating, extracapillary glomerulonephritis, invariably fatal within 27 to 90 days after the first injection. The chief histologic feature is marked fibroepithelial proliferation of Bowman's capsule with crescent formation. The appearance of the lesions resembles the acute, subacute, and chronic stages of human glomerulonephritis, and depends on when the animal was sacrificed. Freund's adjuvant or heterologous GBM alone does not produce such a nephritis. The combination of placental tissue and Freund's adjuvant under the present experimental conditions was also unable to produce a nephritis. The clinical course, increase in nitrogen retention, evolution of renal lesions, and death, all describe a fulminating disease. The disease most characteristically resembles fatal, fulminating human subacute glomerulonephritis. The changes in serum proteins, decrease in serum albumin, and increase in serum globulin, occurred approximately the same in both the GBM-treated and the control adjuvant group. Similar changes have been reported from hyperimmunization alone, and so it is not clear how much these changes are due to immunization and how much is due to the nephritic process. The changes in serum cholesterol were not considered statistically significant. Circulating serum antibodies which localized (by fluorescent antibody technique in vitro) on basement membrane structures of the heterologous donor kidney antigen or which produced nephritis in the heterologous donor species (rat and dog) were found in serum of sheep sick or dying of nephritis. The passive transfer of nephritis by serum antibodies marks the first successful instance of transfer of nephritis by serum antibody to a heterologous species from an animal which had developed nephritis itself. The serum antibodies involved in the transfer of disease to the donor species appear to be unrelated to the mediators of nephritis in the sheep and may represent only the previously known heteronephrotoxic antibodies. By various biologic criteria the sheep nephritis presumably occurs by an autoimmune mechanism. However, it is not known whether the sheep nephritis is mediated by sensitized cells and/or antibodies. The latent period was estimated to end about 16 to 71 days after the first injection. Azotemia was estimated to begin about 17 to 78 days after the first injection. Proteinuria and azotemia began approximately 23 and 13 days before death. The rapid progression to a fatal termination defined the fulminating character of this disease.