Predominant expression of Th2 cytokines and interferon-gamma in xenogeneic cardiac grafts undergoing acute vascular rejection.

BACKGROUND

The Th1 response has been shown to play a role in acute allograft rejection, whereas the Th2 response has been implicated in the protection of allografts. Unlike allografts, the pattern of cytokines in response to solid-organ xenografts has been the subject of limited studies. We investigated intragraft cytokine expression in a concordant cardiac xenograft model (rat-to-mouse) to test if a particular cytokine profile predominates.

METHODS

Intra-abdominal cardiac transplantation was performed using C57BL/10 mice as recipients of PVG.R8 rat hearts. Syngeneic grafts (C57BL/10-to-C75BL/10) served as controls. Cardiac grafts harvested on various days posttransplantation were analyzed for histology and intragraft cytokine expression using reverse-transcriptase polymerase chain reaction.

RESULTS

The grafts in this model were rejected with a mean survival time of 7+/-1 days and showed extensive evidence of acute vascular rejection, consisting of global distortion of myocardial architecture, fewer cellular infiltrates, interstitial hemorrhage with myocyte necrosis thrombosis, and vasculitis with neutrophils and lymphocytes infiltrating vessel walls. Cardiac xenografts predominantly expressed Th2 cytokines, interleukin (IL)-4, IL-10, and transforming growth factor-beta with various kinetics. IL-10 was detectable on day 1 and reached its peak level of expression on day 6 posttransplantation. IL-4 showed minimal and undetectable expression on days 1 and 3 and significant expression on day 6 posttransplantation. Transforming growth factor-beta was expressed moderately on all days examined. The expression of interferon (IFN)-gamma, a Th1 cytokine, was specific to xenografts and showed a gradual increase from days 3 to 6 posttransplantation. In marked contrast, IL-2 showed complete lack of expression.

CONCLUSIONS

Our data demonstrate predominant expression of Th2 cytokines and IFN-gamma in cardiac xenografts undergoing acute vascular rejection. The Th2 cytokines may promote acute vascular rejection by regulating the humoral response, and IFN-gamma may delay, but not prevent, this response.