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

Abstract

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.

Preclinical development of keliximab, a Primatized™ anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies

“…did not differ between normal BALB/c and HuCD4/ Tg mice, indicating that replacement of the murine CD4 gene did not affect histogenesis of the immune system. HuCD4/Tg mice have survived for [18][19][20][21][22][23][24] months in our facilities with no unexpected pathologic developments.…”

Cecal Colonization and Systemic Spread of Candida albicans in Mice Treated with Antibiotics and Dexamethasone

“…100 mg/kg BID. Others have used similarly high doses to facilitate systemic infection with C. albicans in rodents (33,34). Our primary aim was to use dexamethasone to induce systemic spread of C. albicans, and lower doses were not tested.…”

Practical aspects of including functional endpoints in developmental toxicity studies. Case study: immune function in HuCD4 transgenic mice exposed to anti-CD4 MAb in utero

“…14 To determine overall immune competence, survival of selected F1 mice (20/sex per group) was followed after intravenous injection of 1 ± 2£10 6 C. albicans. In the non-specific immunity model, other F1 mice (6/sex per group) were injected intravenously with 2£10 6 C. albicans and 2 hours later, spleens were removed and processed to determine C. albicans colony forming units (CFU) by quantitative culture.…”