Critical role of the calpain/calpastatin balance in acute allograft rejection

Rejection of solid organ allograft involves alloreactive T‐cell expansion. The importance of NF‐κB and NFAT in this process is underscored by the therapeutic efficacy of immunosuppressive agents, which target the two transcription factors. Since calpains, calcium‐activated proteases, are involved in the activation of NF‐κB 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 μ‐calpain, associated with a marked expression of μ‐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 γ‐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.