Nitric Oxide Modulation of the Allograft Response in Vivo

Our previous work detailing the antiproliferative effects of nitric oxide (NO) in various assays of lymphocyte function in vitro led us to examine whether this immunosuppressive effect was also operative in vivo. The efficacy of administration of the NO synthesis inhibitor, aminoguanidine (AG), by various routes was examined. Oral administration as a 1% solution in the drinking water effectively lowered serum NO-2 + NO-3 levels. The effect of AG administration on cytolytic T-lymphocyte (CTL) development in vivo using the sponge matrix allograft model in both rats and mice was examined. Perhaps due to the small amount of NO produced at the graft site, AG administration did not affect CTL activity recovered from the grafts. In a nonlethal model of GvHD, oral administration of AG resulted in a decrease in destruction of host cells that was not associated with any differences in donor antihost CTL activity recovered from the spleens of these mice. Additionally, the proliferative response of T lymphocytes recovered from the spleens of AG-treated GvHD mice was greatly enhanced compared to the response of GvHD mice that did not receive AG. These results indicate that inhibition of NO does not potentiate CTL generation in vivo, which is in contrast to the results that we have seen in vitro. However, NO seems to induce bystander tissue injury in the GvHD process that may account for some host tissue destruction as well as the decreased T-lymphocyte proliferative responses characteristic of the GvHD disease process.