Abstract

Rejection of solid organ allograft involves alloreactive T-cell expansion. The importance of
NF-jB and NFAT in this process is underscored by the therapeutic efficacy of immunosuppressive
agents, which target the two transcription factors. Since calpains, calciumactivated
proteases, are involved in the activation of NF-jB and NFAT, we investigated the
role of calpains in allograft rejection. In human transplant kidneys undergoing acute or
chronic rejection, we show an increased expression of CAPN 1 gene encoding l-calpain,
associated with a marked expression of l-calpain, mainly in infiltrating T cells. To address
the role of calpain in rejection, we used a skin transplant model in transgenic mice
expressing high levels of calpastatin, a calpain-specific inhibitor. We show that calpain
inhibition extended skin allograft survival, from 11 to 20 days. This delay was associated
with a limitation in allograft infiltration by T cells. In vitro, calpain inhibition by calpastatin
transgene expression limited dramatically T-cell migration but, unexpectedly,
increased slightly T-cell proliferation. Amplification of IL-2 signaling via the stabilization
of IL-2R common c-chain provided an explanation for the proliferation response. This is
the first study establishing that calpain inhibition delays allograft rejection by slowing
down T-cell migration rather than proliferation.