Behavioral conditioning of anti-proliferative and immunosuppressive properties of the mTOR inhibitor rapamycin

Suppression of immune functions can be elicited by behavioral conditioning using drugs such as cyclosporine A, cyclophosphamide, or opioids. Nevertheless, little is known regarding the conditioned actions of clinically approved immunosuppressive drugs with distinct cell signaling pathways. The present study tested the assumption to condition immunopharmacological properties of rapamycin (sirolimus), a small-molecule drug widely used as anti-tumor medication and to prevent graft rejection. For this purpose, a conditioned taste avoidance (CTA) paradigm was used, pairing the presentation of a novel taste (saccharin) as conditioned stimulus (CS) with injections of rapamycin as unconditioned stimulus (US). Subsequent re-exposure to the CS at a later time revealed that conditioning with rapamycin induced an only moderate CTA. However, pronounced conditioned immunopharmacological effects were observed, reflected by significantly reduced levels of IL-10 cytokine production and diminished proliferation of splenic CD4(+) and CD8(+) T cells in Dark Agouti and Fischer 344 rats. For one, these findings support earlier observations revealing that not a pronounced CTA but rather re-exposure to the CS or taste itself is essential for conditioned immunosuppression. Moreover, our results provide first evidence that the phenomenon of learned immune responses generalizes across many, if not all, small-molecule drugs with immunosuppressive properties, thereby providing the basis for employing learned immunopharmacological strategies in clinical contexts such as supportive therapy.