Critical role of the calpain/calpastatin balance in acute allograft rejection
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Critical role of the calpain/calpastatin balance in acute allograft rejection. / Letavernier, Emmanuel; Dansou, Boris; Lochner, Matthias; Perez, Joëlle; Bellocq, Agnès; Lindenmeyer, Maja T; Cohen, Clemens D; Haymann, Jean-Philippe; Eberl, Gérard; Baud, Laurent.
in: EUR J IMMUNOL, Jahrgang 41, Nr. 2, 02.2011, S. 473-84.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Critical role of the calpain/calpastatin balance in acute allograft rejection
AU - Letavernier, Emmanuel
AU - Dansou, Boris
AU - Lochner, Matthias
AU - Perez, Joëlle
AU - Bellocq, Agnès
AU - Lindenmeyer, Maja T
AU - Cohen, Clemens D
AU - Haymann, Jean-Philippe
AU - Eberl, Gérard
AU - Baud, Laurent
N1 - Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2011/2
Y1 - 2011/2
N2 - 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.
AB - 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.
KW - Acrylates
KW - Adoptive Transfer
KW - Animals
KW - Calcium-Binding Proteins
KW - Calpain
KW - Cell Differentiation
KW - Cell Movement
KW - Cell Proliferation
KW - Gene Expression
KW - Graft Rejection
KW - Homeodomain Proteins
KW - Humans
KW - Interleukin-2
KW - Kidney
KW - Kidney Transplantation
KW - Lymphocyte Activation
KW - Lymphocyte Culture Test, Mixed
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Mice, Transgenic
KW - NF-kappa B
KW - NFATC Transcription Factors
KW - Skin Transplantation
KW - T-Lymphocytes
KW - T-Lymphocytes, Cytotoxic
KW - Th17 Cells
KW - Transplantation, Homologous
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1002/eji.201040437
DO - 10.1002/eji.201040437
M3 - SCORING: Journal article
C2 - 21268016
VL - 41
SP - 473
EP - 484
JO - EUR J IMMUNOL
JF - EUR J IMMUNOL
SN - 0014-2980
IS - 2
ER -
