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Toxicological Sciences 55, 335-342 (2000)
Copyright © 2000 by the Society of Toxicology

Oral Treatment with Trimethoprim-Sulfamethoxazole and Zidovudine Suppresses Murine Accessory Cell-Dependent Immune Responses

Yvonne R. Freund1, Linda Dousman, James T. MacGregor2 and Nahid Mohagheghpour

SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025-3493

Trimethoprim-sulfamethoxazole (TMP-SMX), commonly used for prophylaxis of Pneumocystis carinii pneumonia (PCP) in AIDS patients, often produces a high incidence of treatment-limiting reactions. We investigated the effect of oral administration of TMP-SMX alone or in combination with the antiretroviral drug zidovudine (ZDV) on hematopoiesis and cellular immunity in BALB/c mice. Daily treatment for 28 days with TMP-SMX (160:800 mg/kg) had no effect on hematopoiesis or the ex vivo proliferative response of splenic T lymphocytes to allogeneic tumor cells (EL-4) or to concanavalin A (ConA), or that of splenic B cells to lipopolysaccharide (LPS). ZDV at 240 mg/kg/day was not immunosuppressive but caused a mild macrocytic anemia. Combined treatment produced severe pancytopenia, a significant drop in splenic cellularity, and a 61% decrease in the percentage of splenic macrophages. The percentage of splenic CD3+ lymphocytes increased 150% in the TMP-SMX + ZDV group, but the ratios of T-cell subsets and the frequency of B cells remained unchanged. Combined drug treatment did not impair the proliferative response of B cells to LPS or that of T cells to EL-4 cells. In concert with the reduction in the percentage of macrophages, the proliferative response of T lymphocytes to ConA decreased significantly. Optimal ConA-induced T-cell proliferation requires the participation of accessory cells (AC) (e.g., macrophages); EL-4 cells are able to function as AC. These data indicate that ZDV synergizes with TMP-SMX, causing severe hematotoxicity and suppressing AC-dependent immune function, and suggest that this therapeutic regimen may contribute to the immune deterioration in AIDS patients.

Key Words: trimethoprim-sulfamethoxazole; zidovudine; Pneumocystis carinii pneumonia; immunosuppression; accessory cells.


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D. J. Feola and B. A. Garvy
Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses to Pneumocystis murina Infection in Healthy Mice
Clin. Vaccine Immunol., February 1, 2006; 13(2): 193 - 201.
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