The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program (NTP). The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see http://ntp.niehs.nih.gov/ntp/htdocs/levels/09-3566%20NTP-ITOX-R1.pdf). The findings and conclusions for this study should not be construed to represent the views of the NTP or the US Government.
Immunotoxicity Studies of 2',3'-Dideoxyinosine (CAS No. 69655-05-6) in Female B6C3F1 Mice
NTP Report Number IMM94006
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.
Spleen Antibody Cell Response to sRBC in Female B6C3F1 Mice
Treated with ddI for 180 Days
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.
SUMMARY TABLE FOR TOXICOLOGY STUDIES
|Body Weight||Decrease in body weight and body weight gain in mice treated with 1000 mg/kg/day.|
|Gross Pathology||Decrease in spleen and thymus size in mice treated with 1000 mg/kg/day|
|Histopathology||Tissues maintained in buffered formalin|
|Brain||Increase||67%||1000 mg/kg||% Bdy Wt|
|Liver||Increase||31%||1000 mg/kg||% Bdy Wt|
|Spleen||Decrease||-42%||1000 mg/kg||Organ/Brain Ratio|
|Thymus||Decrease||-64%||1000 mg/kg||Organ/Brain Ratio|
|Kidney||Increase||48%||1000 mg/kg||% Bdy Wt|
|Total Protein||Decrease||-6%||500 mg/kg|
|DNA Synthesis||No Effect|
SUMMARY TABLE FOR IMMUNOLOGY STUDIES
|Surface Markers/Absolute Values|
|Ig+||Decrease||-38%||1000 mg/kg||Function of|
|CD3+||Decrease||-67%||1000 mg/kg||a decrease|
|CD4+CD8-||Decrease||-54%||1000 mg/kg||in spleen|
|CD4-CD8+||Decrease||-65%||1000 mg/kg||cell number.|
|IgM Humoral Immune Response to Sheep Erythrocytes|
|IgM AFC to sRBC||Decrease||-87%||1000 mg/kg|
|Serum Titers to sRBC||Decrease||-86%||1000 mg/kg|
|Proliferation Assays, i.e. Mitogen, Mixed Leukocyte Response|
|Mito||Decrease||-65%||1000 mg/kg||Con A|
|Cytotoxic T Lymphocyte Activity|
|NK Cell Activity|
Report Date: February 1996