Relative roles of Th1 and Th17 effector cells in allograft rejection

Atalar, Kerem; Afzali, Behdad; Lord, Graham M.; Lombardi, Giovanna

doi:10.1097/mot.0b013e32831b70c2

Cited by 59 publications

(46 citation statements)

References 69 publications

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“…A proper role of IL-17 in allograft rejection has recently been proposed [28]. Nevertheless, its importance would be limited to rejection responses in older transplant recipients [29] and in case of minor antigen disparity [30].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, in vitro experiments showed that the calpain inhibition by calpastatin transgene affected mainly the IL-17 expression. One possible explanation for this finding is again that calpastatin limited proteolytic cleavage of the g c chain in IL-2 receptor, thereby amplifying IL-2-dependent inhibition of T H 17 generation.A proper role of IL-17 in allograft rejection has recently been proposed [28]. Nevertheless, its importance would be limited to rejection responses in older transplant recipients [29] and in case of minor antigen disparity [30].…”

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confidence: 99%

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

et al. 2010

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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.Key words: Allograft . Calpain . Calpastatin . T cells IntroductionSolid organ transplantation represents an important means of treating end stage organ failure. However, this strategy is limited by the immune response mounted by the recipient against donor tissue. Acute allograft rejection involves T cells of the adaptive immune system in addition to cells of the innate immune system [1]. T-cell receptor (TCR) engagement in naïve T cells initiates changes in gene expression that are essential for the generation of effector T cells. They require the activation of transcription factors, primarily NF-kB and NFAT [2,3]. TCR/CD28-induced NF-kB activation characteristically elicits the expression of both IL-2 and IL-2 receptor a chain together with the antiapoptotic molecule Bcl-x L [2]. NFAT, which is activated by the calmodulin-dependent phosphatase calcineurin, is also required for the expression of the IL-2 gene through its interaction with proteins of the AP1 family of transcription factors [3]. Given the importance of these two pathways in the generation Ã These authors contributed equally to this work. Eur. J. Immunol. 2011. 41: 473-484 DOI 10.1002 Leukocyte signaling 473 of effector T cells, a number of different pharmacological inhibitors of NF-kB and/or calcineurin/NFAT are currently used as immunosuppressive agents in transplantation, including steroids, cyclosporin A and tacrolimus (FK-506) [4]. Calpains are calcium-activated neutral cysteine proteases [5]. Two major isoforms, calpain m (or I) and calpain m (or II), which require micromolar and millimolar Ca 21 concentrations for activity, respectively, are ubiquitously expressed, whereas the ...

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Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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“…In kidney transplantation, IL-17 transcripts are observed in kidney transplant biopsy specimens presented with rejection (15). IL-17-producing graft-infiltrating T cells have been detected in rejected allografts, Th17 and Kidney Graft Rejection especially those undergoing acute antibody-mediated rejection (16,17). Therefore, a large number of IL-17-positive cells in kidney allografts during an acute rejection episode seems to be a strong factor of poor graft outcome (18).…”

Section: Discussionmentioning

confidence: 99%

Th-17 Alloimmune Responses in Renal Allograft Biopsies From Recipients of Kidney Transplants Using Extended Criteria Donors During Acute T Cell–Mediated Rejection

Matignon

Aissat

Canouï‐Poitrine

et al. 2015

American Journal of Transplantation

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“…It has been shown that IL-17A-expressing CD4 + T cells, more than IFN-g-producing CD4 + Th1 cells, play an important role in rejection and vasculopathy in clinical solid organ transplantation [21][22][23]. Twelve-month transplant specimens from CsA-treated patients showed important mononuclear cell infiltrates in which IL-17A-producing CD4 + T cells were clearly evident, even in the absence of acute rejection criteria; this process was accompanied by fibrosis and hyaline material.…”

Section: Discussionmentioning

confidence: 99%