2',3'-DIDEOXYINOSINE INHIBITS THE HUMORAL IMMUNE-RESPONSE IN FEMALE B6C3F1 MICE BY TARGETING THE B-LYMPHOCYTE

2',3'-Dideoxyinosine (ddI) is a purine nucleoside analog currently bei ng used for the treatment of HIV-positive individuals and patients wit h AIDS, Preliminary immunotoxicity studies have shown that a consequen ce of ddI treatment in female B6C3F1 mice is the inhibition of the hum oral immune response, This effect was dose dependent in a range of 100 to 1000 mg/kg with a no observed adverse effect level of less than 10 0 mg/kg for a 28-day treatment period, These studies were undertaken t o investigate the immune cell target of ddI and to determine the mecha nism of this toxicity. B6C3F1 mice were treated with 1000 mg/kg/day by oral gavage for 28 days. The B lymphocyte was identified as the cellu lar target of ddI through separation-reconstitution experiments of the adherent and nonadherent cell populations and of the T and B lymphocy te populations, These studies revealed a deficit in the ability of the nonadherent cells from ddI-treated mice to mount a normal antibody re sponse to sRBC, A further separation of the nonadherent cells into T a nd B cells revealed a decreased ability of ddI-treated B cells to deve lop specific humoral immunity, Additional studies were undertaken to d etermine the mechanism by which ddI is affecting the B cell. Surface m arker analysis of splenocytes revealed no difference in the cell popul ations between vehicle-and ddI-treated mice, B cell proliferation was also unaffected as shown by incubation with either a polyclonal stimul ator, lipopolysaccharide, or anti-IgM plus IL-4. These results indicat e that the primary cellular target of ddI is the B lymphocyte. (C) 199 7 Academic Press.