The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.
2',3'-Dideoxyinosine (ddI) is presently being used for the treatment of HIV positive individuals and for the treatment of AIDS patients. Previous studies by Luster et al. showed that some of the anti-HIV drugs had adverse effects on the immune system. Cao et al. showed the B lymphocyte was a target for 2,3-dideoxyadenosine. 2,3-Dideoxyadenosine is metabolized to ddI. Because of the long duration of treatment of humans, a six month twice daily repeat dose study of ddI was recommended by the Food and Drug Administration.
The studies were conducted in female B6C3F1 mice. The animals were administered 2',3'-dideoxyinosine twice daily for a 6 month period by oral gavage. The in-life phase began June 22, 1994 and was completed on January 31, 1995. 2',3'-Dideoxyinosine was prepared as a suspension in Maalox Therapeutic Concentrate (Maalox T C).
The baseline toxicology studies are summarized in Table ES-1. The major adverse effect related to the baseline toxicology is a profound effect on body weight gain in the high dose group. Mice treated with 1000 mg/kg/day of ddI gained weight equivalent to controls for 3 weeks and then did not gain weight over the remainder of the treatment period. Spleen and thymus weights were decreased dose dependently.
Table ES-2 summarizes the immunology studies.Spleen phenotyping showed a decrease in both T and B cells consistent with a decrease in spleen cell number. There was minimal effect on the percent of T cells, subsets of T cells or B cells.
The key data are graphically represented in Figure ES-1. The most sensitive action of ddI was on the ability of mice to respond to the T-dependent antigen sheep erythrocytes (sRBC). Antibody producing cells and antibody titers in mice treated with ddI were suppressed by as much as 86%. The lowest dose of ddI, 100 mg/kg/day, produced a 44% reduction in the humoral immune response. Thus, the NOAEL is below 100 mg/kg/day. The other immune functions that were suppressed were spleen cell responsiveness to allogeneic cells (MLR) and to the T cell mitogen, Concanavalin A. The NOAEL for these functions was 250 mg/kg/day. ddI produced no changes in innate immunity as measured by natural killer cell and macrophage activity.
The results of the 2',3'-dideoxyinosine studies demonstrate that, in the female B6C3F1 mouse, treatment with 2',3'-dideoxyinosine, administered by oral gavage for 180 days, has a profound and selective effect on the immune system.