Experimental and clinical allogeneic heart transplant rejection : Correlations between histology and immune reactivity detected by cytokine messenger RNA

Background : Cytokines produced by host cells infiltrating allogeneic transplants are critical determinants of graft rejection but information on cytokine production during graft rejection remains limited. No reported study on cytokine profiles has compared experimental allograft rejection induced by withdrawal of cyclosporine with clinical transplant rejection that occurs in the presence of therapeutic levels of cyclosporine. Methods : Functional activities of allograft-infiltrating host cells in sequential endomyocardial biopsies obtained before, during, and after acute heart transplant rejection were determined with the use of the reverse transcriptase-polymerase chain reaction to detect cytokine messenger RNA. These results were correlated with histologic findings in both an experimental canine model of heart transplant rejection and in clinical human heart transplant recipients. Results : When experimental rejection was induced by withdrawal of immunosuppression, rejection was characterized by the presence of mRNA encoding CD4, CD8, interleukin-2 (but not interleukin-4), interleukin-2 receptor, and tumor necrosis factor-β. These findings are consistent with a classic T-helper, T-cytotoxic cell-mediated response. However, the cytokine profile of human, clinical heart transplant rejection occurring in the presence of therapeutic levels of immunosuppression differed strikingly. In clinical rejection in human beings, histologic evidence of rejection was not associated with detectable interleukin-2 or interleukin-2 receptor mRNA. Conclusions : Human, clinical heart rejection can occur in the absence of locally produced interleukin-2 ; the degree of immunosuppression achieved with cyclosporine A may explain the different results obtained in the canine withdrawal model versus human clinical allograft rejection.