Oral treatment with trimethoprim-sulfamethoxazole and zidovudine suppresses murine accessory cell-dependent immune responses.
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.
Freund
Y R
YR
SRI International, Menlo Park, California 94025-3493, USA. yvonne.freund@sri.com
Dousman
L
L
MacGregor
J T
JT
Mohagheghpour
N
N
D000284:Administration, Oral; D000748:Anemia, Macrocytic / Q000139:chemically induced; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000187:drug effects*; D003208:Concanavalin A / Q000494:pharmacology; D004338:Drug Combinations; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D007111:Immunity, Cellular / Q000187:drug effects; D007165:Immunosuppression Therapy; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D010198:Pancytopenia / Q000139:chemically induced; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000008:administration & dosage / Q000494:pharmacology*
D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D004338:Drug Combinations; D008070:Lipopolysaccharides; D003208:Concanavalin A; D015215:Zidovudine; D015662:Trimethoprim, Sulfamethoxazole Drug Combination