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.
INSERM, UMR S 702, Paris, France.
Emmanuel
E
Letavernier
Boris
B
Dansou
Matthias
M
Lochner
Joëlle
J
Perez
Agnès
A
Bellocq
Maja T
MT
Lindenmeyer
Clemens D
CD
Cohen
Jean-Philippe
JP
Haymann
Gérard
G
Eberl
Laurent
L
Baud
D000179:Acrylates / Q000627:therapeutic use; D019264:Adoptive Transfer; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
D000179:Acrylates; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C100442:PD 150606; C064658:RAG-1 protein; C033668:calpastatin; D002154:Calpain; C484806:CAPN1 protein, human; C527669:CAPNS1 protein, human; C569870:CAPN2 protein, human