Immunotoxicity of 2′, 3′-Dideoxyinosine in Female B6C3F1 Mice

Details

• Personal Author:
  Brown RD ; Butterworth LF ; McCay JA ; Meade JB ; Munson AE ; Musgrove DL ; Phillips KE ; White, Kathy L. ; Wilson S
• Description:
  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 viral reverse transcriptase and termination of DNA synthesis. However, each of these drugs has toxicity associated with its use. A previous immunotoxicological evaluation of 2',3'-dideoxyadenosine (ddA), the parent 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 innate 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 toxicity related to treatment with ddI except for a decrease in body weight in the group treated with the highest dose of ddI for 180 days. Overall, 6 months of treatment with ddI showed minimal effects on specific organs with the exception of the spleen and thymus. ddI selectively targets the immune system, with assays that challenge humoral immunity being more affected than those testing cell-mediated immunity. Innate immunity was unaffected by ddI treatment. Cell-mediated immunity, as measured by proliferative response to allogeneic cells (MLR) and the T cell mitogen (Concanavalin A), was moderately suppressed. There were no ddI associated effects on NK function or macrophage function as measured by the vascular clearance rate and phagocytic uptake of the tissue macrophages. The most sensitive indicator of ddI-induced immunotoxicity is suppression of the response to the T-dependent antigen, sheep red blood cells (sRBC). The No Observable Adverse Effect Level (NOAEL) 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 seen 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. [Description provided by NIOSH]
• Subjects:
  Acquired Immunodeficiency Syndrome Animals Blood HIV Immune System Laboratories Occupational Health Safety
• Keywords:
  AIDS-virus Animal-studies Cellular-reactions Immune-reaction Immune-system-disorders Immunotoxins Laboratory-animals Lymphocytes
• ISSN:
  0148-0545
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; Virginia ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  189-228
• Volume:
  20
• Issue:
  3
• NIOSHTIC Number:
  nn:20033930
• Citation:
  Drug Chem Toxicol 1997 Aug; 20(3):189-228
• Federal Fiscal Year:
  1997
• Peer Reviewed:
  True
• Source Full Name:
  Drug and Chemical Toxicology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:9d9957dcbcec9ef5db4020fba1ecf34cebeaf339a526d76d570bdcd80df4d12c978c12c0434b8fbd362b69544a547c6132ab2a1b4388f301a351a7c558e1d621
• Download URL:
  https://stacks.cdc.gov/view/cdc/189329/cdc_189329_DS1.pdf
• File Type:
  [PDF - 1.58 MB ]