IMMUNOTOXICITY OF 2',3'-DIDEOXYINOSINE IN FEMALE B6C3F1 MICE

2',3'-dideoxyinosine (ddI) is one of several purine analogues used for the treatment of HIV and the acquired immunodeficiency syndrome (AIDS ). These nucleoside analogues are promising in their inhibition of vir al reverse transcriptase and termination of DNA synthesis. However, ea ch of these drugs has toxicity associated with its use. A previous imm unotoxicological evaluation of 2',3'-dideoxyadenosine (ddA), the paren t compound of ddI, showed that ddA suppresses humoral immunity. These studies were undertaken to determine the potential for immunotoxicity due to treatment with ddI. This evaluation included an assessment of i nnate and acquired immunity after exposure to ddI (100, 250, 500, and 1000 mg/kg/day) for 14, 28 or 180 days. There were no overt signs of t oxicity related to treatment with ddI except for a decrease in body we ight in the group treated with the highest dose of ddI for 180 days. O verall, 6 months of treatment with ddI showed minimal effects on speci fic organs with the exception of the spleen and thymus. ddI selectivel y targets the immune system, with assays that challenge humoral immuni ty being more affected than those testing cell-mediated immunity. Inna te immunity was unaffected by ddI treatment. Cell-mediated immunity, a s measured by proliferative response to allogeneic cells (MLR) and the T cell mitogen (Concanavalin A), was moderately suppressed. There wer e no ddI associated effects on NK function or macrophage function as m easured by the vascular clearance rate and phagocytic uptake of the ti ssue macrophages. The most sensitive indicator of ddI-induced immunoto xicity is suppression of the response to the T-dependent antigen, shee p red blood cells (sRBC). The No Observable Adverse Effect Level (NOAE L) for toxicity to the immune system following 14 days of exposure to ddI is 250 mg/kg. A suppression of the humoral immune response was see n at the lowest dose tested after treatment for 28 and 180 days. Thus, the NOAEL for both of these treatment periods is below 100 mg/kg/day.