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 being used for the treatment of HIV-positive individuals and patients with AIDS. Preliminary immunotoxicity studies have shown that a consequence of ddI treatment in female B6C3F1 mice is the inhibition of the humoral 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 100 mg/kg for a 28-day treatment period. These studies were undertaken to investigate the immune cell target of ddI and to determine the mechanism 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 cellular target of ddI through separation-reconstitution experiments of the adherent and nonadherent cell populations and of the T and B lymphocyte populations. These studies revealed a deficit in the ability of the nonadherent cells from ddI-treated mice to mount a normal antibody response to sRBC. A further separation of the nonadherent cells into T and B cells revealed a decreased ability of ddI-treated B cells to develop specific humoral immunity. Additional studies were undertaken to determine the mechanism by which ddI is affecting the B cell. Surface marker analysis of splenocytes revealed no difference in the cell populations between vehicle- and ddI-treated mice. B cell proliferation was also unaffected as shown by incubation with either a polyclonal stimulator, lipopolysaccharide, or anti-IgM plus IL-4. These results indicate that the primary cellular target of ddI is the B lymphocyte.
Phillips
K E
KE
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-0613, USA.
Munson
A E
AE
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D003433:Crosses, Genetic; D016049:Didanosine / Q000633:toxicity*; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000187:drug effects; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000187:drug effects*; D007441:Intubation, Gastrointestinal; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL
D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016049:Didanosine