Analysis of the Th1/Th2 paradigm in transplantation: Interferon-gamma deficiency converts Th1-type proislet allograft rejection to a Th2-type xenograft-like response

The rejection mechanisms for fetal proislet allografts and pig proislet xen ografts in mice are characterized by different intragraft cytokine mRNA pro files and cellular responses. Allograft rejection is predominantly CD8 T-ce ll-dependent and is associated with a Th1-type cytokine pattern (i.e., IFN- gamma, IL-2 but no IL-4 or IL-5 mRNA). In contrast, xenograft rejection is CD4 T-cell-dependent and is accompanied by a strong Th2-type response (i.e. , enhanced expression of IL-4 and IL-5 mRNA) and by marked eosinophil accum ulation at the graft site. We have now examined and compared the regulatory role of IFN-gamma in both proislet allograft and xenograft rejection proce sses. The histopathology and intragraft cytokine mRNA profile of BALB/c (H- 2(d)) proislet allografts were examined in IFN-gamma-deficient and wild-typ e C57BL/6J recipient mice. The survival of pig proislet xenografts was also assessed in IFN-gamma -/- and wild-type hosts. Both proislet allo-grafts a nd xenografts were acutely rejected in IFN-gamma -/- and wild-type mice. Un like the conventional allograft reaction, which lacks eosinophil infiltrati on, the rejection of proislet allografts in IFN-gamma-deficient hosts corre lated with intragraft expression of IL-4 and IL-5 mRNA (i.e., a Th2-type re sponse) and eosinophil recruitment. The rejection of proislet allografts an d xenografts can therefore occur by IFN-gamma-independent pathways; IFN-gam ma, however, regulates the pathology of the allograft reaction but not the xenograft response. The immune destruction of proislet allografts is not pr evented by Th2 cytokine gene expression; instead, the latter correlated wit h the recruitment of unconventional inflammatory cells (eosinophils), which may play an accessory role in effecting graft injury. Significantly, the T h1-to-Th2-like switch resulted in the novel conversion of an allograft reje ction reaction into a xenograft-like rejection process.