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Single-Organism Model of Host Defense against Infection: A Novel Immunotoxicologic Approach to Evaluate Immunomodulatory Drugs

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

Toxicologic Pathology, Vol. 25, No. 4, 351-362 (1997)
DOI: 10.1177/019262339702500403


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