Glucocorticoid-Induced TNFR-Related Protein Stimulation Reverses Cardiac Allograft Acceptance Induced by CD40-CD40L Blockade

Abstract EN

CD40-CD40L blockade has potent immunosuppressive effects in cardiac allograft rejection but is less effective in the presence of inflammatory signals.

To better understand the factors that mediate CD40-CD40L blockade-resistant rejection, we studied the effects of stimulation through glucocorticoid-induced TNFR-related protein (GITR), a costimulatory protein expressed by regulatory and effector T cells.

Stimulation of CD40−/− or wild-type recipient mice treated with anti-CD40L mAb (WT+anti-CD40L) and with agonistic anti-GITR mAb resulted in cardiac allograft rejection.

GITR stimulation did not induce rejection once long-term graft acceptance was established.

In vitro, GITR stimulation increased proliferation of effector T cells and decreased regulatory T cell (Treg) differentiation in both treatment groups.

GITR-stimulated CD40−/− recipients rejected their allografts more rapidly compared to GITR-stimulated WT+anti-CD40L recipients, and this rejection, characterized by a robust Th2 response and significant eosinophilic infiltrate, could be mediated by CD4+ T cells alone.

In contrast, both CD4+ and CD8+ T cells were required to induce rejection in GITR-stimulated WT+anti-CD40L-treated recipients, and the pathology of rejection was less severe.

Hence, early GITR stimulation could initiate graft rejection despite CD40 deficiency or anti-CD40L mAb treatment, though the recipient response was dependent on the mechanism of CD40-CD40L disruption.