Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses toPneumocystis murinaInfection in Healthy Mice

Abstract

We have previously shown that zidovudine plus sulfamethoxazole-trimethoprim exposure decreases immune cell populations in the bone marrow of healthy mice by inducing apoptosis. The hypothesis of the current work was that this toxicity would have an adverse impact on the immune response. To determine this, BALB/c mice were treated with zidovudine, sulfamethoxazole-trimethoprim, the combination of both drugs, or vehicle only (control) via oral gavage for 21 days. On day 4 after dosing completion, the mice were infected intratracheally with 1x10(7) Pneumocystis murina organisms. Immune cell populations (in lung digest, bronchoalveolar lavage fluid, tracheobronchial lymph node, and bone marrow samples), the lung Pneumocystis burden, and serum Pneumocystis-specific antibody titers were determined at days 6, 10, and 20 postinfection. While total bone marrow cellularity was recovered by day 6 postinfection in the combination exposure group, B-cell numbers did not recover until 10 days postinfection, primarily due to the persistent depletion of the late pre-B-cell phenotype. The numbers of CD4+ and CD8+ T cells, as well as the numbers of total B cells and activated B cells in tracheobronchial lymph nodes, were decreased at days 10 and 20 as a result of zidovudine plus sulfamethoxazole-trimethoprim exposure compared to the numbers in the control group. No significant differences in lung lavage or lung digest cell populations were observed. There was a trend of a delay in Pneumocystis clearance in the combination treatment group, and Pneumocystis-specific serum immunoglobulin G titers were reduced at day 20 postinfection. Together, these data indicate that the combination of zidovudine and sulfamethoxazole-trimethoprim adversely affects the humoral immune response to Pneumocystis.