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Am J Physiol Regul Integr Comp Physiol 276: R1710-R1717, 1999;
0363-6119/99 $5.00
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Vol. 276, Issue 6, R1710-R1717, June 1999

Conditioned immunosuppression makes subtherapeutic cyclosporin effective via splenic innervation

Michael S. Exton1, Marc Schult2, Stefan Donath3, Tim Strubel3, Ulrike Bode3, Adriana del Rey4, Jürgen Westermann3, and Manfred Schedlowski1

1 Institute for Medical Psychology, Faculty of Medicine, University of Essen, 45122 Essen; Divisions of 2 Abdominal and Transplantation Surgery and 3 Functional and Applied Anatomy, Hannover Medical School, 30623 Hannover; and 4 Institute of Physiology, Division of Immunophysiology, Philipps-University Marburg, 35037 Marburg, Germany

The present study investigated the mechanisms by which conditioned immunosuppression enhances the effectiveness of cyclosporin A (CsA) treatment in prolonging heart allograft survival. Dark Agouti rats that were administered subtherapeutic CsA (7 × 2 mg/kg on alternate days) rejected heart allografts at the same time as non-CsA-treated rats. The addition of a behavioral conditioning regimen (conditioned stimulus, saccharin; unconditioned stimulus, 20 mg/kg CsA) to the subtherapeutic CsA protocol produced a significant prolongation 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 treatment reduce interleukin-2 and interferon (IFN)-gamma in the supernatant of proliferating splenocytes. Additionally, therapeutic CsA treatment decreased 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 survival by inhibiting the release of these cytokines in the spleen via sympathetic innervation, supplementing the inhibited cytokine production induced by CsA treatment.

classical conditioning; heart transplantation; cytokine; interferon-gamma ; graft survival


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M. S. Exton, A. Elfers, W.-Y. Jeong, D. F. Bull, J. Westermann, and M. Schedlowski
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