Fc-dependent depletion of activated T cells occurs through CD40L-specific antibody rather than costimulation blockade

Monk, Nicola J.; Hargreaves, Roseanna; Marsh, James E.; Farrar, Conrad A.; Sacks, Steven H.; Millrain, Maggie; Simpson, Elizabeth; Dyson, Julian; Jurčević, Stipo

doi:10.1038/nm931

Cited by 135 publications

(111 citation statements)

References 41 publications

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“…The therapeutic administration of this antibody antagonizes CD40L/CD40 interactions, but more importantly, it also depletes recently activated alloreactive T cells expressing CD40L and alloreactive Tfh cells, which consequently abrogates T-/B-cell collaborations and antibody production. 29,30 The antibodies used in this study that were raised against BTLA/HVEM pathway molecules were both rat IgG 2a isotype antibodies. Rat IgG 2a isotype antibodies do not efficiently bind to the mouse FccRI (CD64) and FccRIV (CD16.2) proteins, which are the two major Fc receptors involved in antibody-dependent cellular cytotoxicity that is mediated by natural killer cells and myeloid cells 55 (Li F and Ravetch JV, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Antibodies for in vivo use and flow cytometry Hybridoma cell lines that secreted an anti-HVEM monoclonal antibody (mAb) (clone 6C9, blocking antibody of the HVEM/ BTLA interaction), 20 anti-BTLA mAb (clone 4G12b, downmodulates BTLA receptor expression), 21,27 anti-CD40L mAb (clone MR1, blocking/depleting antibody) [28][29][30] or an isotype-matched control rat IgG 2a (antiplant cytokinin, clone AFRC-MAC-157) antibody were grown in Serum free medium (SFM) medium Gibco (Grand Island, NY 14072, USA) supplemented with IgG-depleted foetal calf serum (less than 1%) in spinner flasks. Cell culture supernatants were pre-filtered and then loaded onto a protein G-Sepharose column, and affinity chromatography was performed for the purification of the immunoglobulins.…”

Section: Animalsmentioning

confidence: 99%

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T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

et al. 2016

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Section: Discussionmentioning

confidence: 99%

“…We have demonstrated an extended skin allograft survival in transgenic mice. Given that skin allografts are more resistant to tolerance induction than other tissues [23] and that prolonged graft survival across C57BL/6 to BALB/C combination is difficult to obtain in the absence of immunosuppressive agents [24], these results are particularly conclusive.The key finding to emerge from our study is that calpain inhibition in CalpTG mice is responsible for dampening down T-cell infiltration in skin allografts. This is not attributable to the sequestration of circulating T cells into the secondary lymphoid tissues, a likely mechanism beyond the immunosuppressive effect of FTY720 [25].…”

mentioning

confidence: 99%

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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“…The marked decrease in T cell priming after combination therapy could be due to depletion of alloreactive clones. Both DST an anti-CD40L have both been shown to act at least in part through depletion of CD8 and CD4 cells (9,20,21). To determine whether DST enhances graft survival mediated by anti-CD154 and anti-CD45RB.…”

Section: Significant Loss Of Alloreactivity Induced By Dst Plus Anti-mentioning

confidence: 99%

Requirements for induction and maintenance of peripheral tolerance in stringent allograft models

Sho

Kishimoto²,

Harada³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Peripheral tolerance can be achieved in many but not all murine allograft models. The requirements for controlling more aggressive immune responsiveness and generating peripheral tolerance in stringent allograft models are unknown. Understanding these requirements will provide insight toward ultimately achieving tolerance in humans, which are also resistant. We now demonstrate that the combination of donor-specific transfusion, anti-CD45RB, and anti-CD154 uniformly achieves >90-d survival of BALB͞c skin allografts on C57BL͞6 recipients. Recipients exhibit marked hyporesponsiveness to alloantigen in vitro. In distinct contrast to less rigorous models, engraftment remains absolutely dependent on cytotoxic T lymphocyte antigen 4 signaling, even after grafts are healed, suggesting that prolonged engraftment cannot simply be attributed to more effective depletion of alloreactive T cells but is actively maintained by regulation. Concordantly, we show that both CD4 and CD8 regulatory cells are required and can transfer donor-specific tolerance to naïve recipients. Nonetheless, most recipients ultimately develop gradual graft loss (median survival time ‫؍‬ 140 d), suggesting that alloreactive cells emerging from the thymus eventually overwhelm regulatory capacity. In agreement, adding thymectomy to the regimen results in permanent engraftment (>250 d) and donor-specific tolerance not observed previously in this model. These results highlight the potency of both CD4 and CD8 regulatory cells but also suggest that in stringent settings, regulatory T cell longevity and capacity for infectious tolerance compete with prolonged graft immunogenicity and thymic output. These results provide insight into the mechanisms of tolerance in stringent models and provide a rational basis for innovative tolerogenic strategies in humans.transplantation ͉ rodent ͉ CD4 cell ͉ CD8 cell ͉ regulatory T cell

show abstract

Fc-dependent depletion of activated T cells occurs through CD40L-specific antibody rather than costimulation blockade

Cited by 135 publications

References 41 publications

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

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

Requirements for induction and maintenance of peripheral tolerance in stringent allograft models

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