Conditioned immunosuppression makes subtherapeutic cyclosporin effective via splenic innervation

The present study investigated the mechanisms by which conditioned immunosu ppression enhances the effectiveness of cyclosporin A (CsA) treatment in pr olonging heart allograft survival. Dark Agouti rats that were administered subtherapeutic CsA (7 x 2 mg/kg on alternate days) rejected heart allograft s at the same time as non-CsA-treated rats. The addition of a behavioral co nditioning regimen (conditioned stimulus, saccharin; unconditioned stimulus , 20 mg/kg CsA) to the subtherapeutic CsA protocol produced a significant p rolongation of graft survival, including long-term survival (>100 days) in 20% of the animals. Prior sympathetic denervation of the spleen completely blocked this effect. In nontransplanted rats both conditioning and CsA trea tment reduce interleukin-2 and interferon (IFN)-gamma in the supernatant of proliferating splenocytes. Additionally, therapeutic CsA treatment decreas ed the number of IFN-gamma-producing CD4(+) naive and memory T cells in the spleen. In contrast, behavioral conditioning increased that number. These data indicate that behavioral conditioning prolongs heart allograft surviva l by inhibiting the release of these cytokines in the spleen via sympatheti c innervation, supplementing the inhibited cytokine production induced by C sA treatment.