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Single-Organism Model of Host Defense against Infection: A Novel Immunotoxicologic Approach to Evaluate Immunomodulatory Drugs
Danuta J. Herzyk
Department of Toxicology, SmithKline Beecham Pharmaceutical
Elizabeth V. Ruggieri
Department of Toxicology, SmithKline Beecham Pharmaceutical
Lolita Cunningham
Department of Toxicology, SmithKline Beecham Pharmaceutical
Rodd Polsky
Department of Toxicology, SmithKline Beecham Pharmaceutical
Christopher Herold
Department of Toxicology, SmithKline Beecham Pharmaceutical
Anne M. Klinkner
Department of Toxicology, SmithKline Beecham Pharmaceutical
Alison Badger
Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406
William D. Kerns
Department of Toxicology, SmithKline Beecham Pharmaceutical
Peter J. Bugelski
Department of Toxicology, SmithKline Beecham Pharmaceutical, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
The immunotoxicologic effects of drugs on host defense have been studied widely using various animal models of infection. Here we describe a new approach to testing host defense by using a single organism (Candida albicans) in CBA/J mice. The model is configured to test 3 effector systems via different routes of inoculation to stimulate different effector arms of the immune response. Nonspecific immunity was evaluated by C. albicans colony-forming unit (CFU) count from the spleen at 2 hr (uptake) and  22 hr (clearance) following intravenous inoculation. Cell-mediated immunity was assessed by CFU count from an intramuscular injection site 6 days postinoculation. Humoral immunity was assessed by anti- Candida antibody titer, following multiple subcutaneous immunizations with C. albicans. Finally, overall immunity was evaluated following intravenous injection using survival as the endpoint. Histopathological, immunohistochemical, and electron microscopic evaluation of selected tissues revealed the involvement of the expected cell types in the different effector systems. Several immunomodulatory drugs—dexamethasone, cyclosporine, liposomal muramyltripeptide phosphatidylethanolamine, and SK&F 105685—were evaluated in the C. albicans model. Dexamethasone impaired host defense against C. albicans by suppressing all endpoints measured. Similarly, cyclosporine showed broad immunosuppressive activity, with the exception of yeast uptake from the spleen. In contrast, muramyl tripeptide-phosphatidylethanolamine enhanced all but cell-mediated immunity to C. albicans. SK&F 105685 displayed both stimulatory and inhibitory effects on immune responses to the infection. Our studies demonstrate that a single organism-based approach can be a useful method for evaluating the immunological hazards of drugs on host resistance to infection.
Key Words: Anti-Candida antibody • C. albicans • clearance from local infection • immunoactive drugs • spleen uptake • survival • systemic infection
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Toxicologic Pathology, Vol. 25, No. 4,
351-362 (1997)
DOI: 10.1177/019262339702500403
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