Induction of antigen-specific tolerance by cyclosporin A

Recently, we reported preliminary evidence for the induction of tolerance in vivo by cyclosporin A (CSA) during a persistent virus infection in rats. In the present communication, those observations are verified and the findings extended to the functional level of cell-mediated immunity. Mice infected intracerebrally with lymphocytic choriomeningitis virus (LCMV) normally die from a fatal immune-mediated disease after 6-8 days but they do not succumb if treated intraperitoneally with 50 mg/kg/day of CSA. Immunosuppression initiated one day before infection and continued for at least two consecutive weeks resulted in the absence of immunopathologic disease of the brain and in the survival of mice, which were found to be persistently infected virus carriers. In these animals, no cytotoxic T cell activity could be detected. The effect of CSA was not due to a toxic effect on the immune response since immune reactivity was restored as early as 4 days after discontinuation of the drug in control animals. Neither secondary in vitro nor in vivo restimulation resulted in the generation of a cellular antiviral immune response. Cytotoxic T cell reactivity to third-party antigen, however, could be detected, although somewhat delayed. Additionally, spleen cells from CSA-treated mice did not clear the virus from LCMV-infected recipients upon adoptive transfer, whereas spleen cells from LCMV immune mice completely eliminated virus infection in carrier mice. However, mice immunosuppressed with CSA and infected with vesicular stomatitis virus (VSV) did not generate a primary immune response but were immunologically fully reactive to challenge infection, providing evidence for the absence of tolerance and the presence of antigen-specific temporal unresponsiveness. Thus, as exemplified by VSV infection in which the virus does not replicate to considerable titers in mice and viral antigens do not persist, the presence of the foreign antigen for prolonged periods of time could be shown to be a conditio sine qua non for CSA-induced tolerance.