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

Matignon, Marie; Aissat, Abdel; Canouï‐Poitrine, Florence; Grondin, Cynthia; Pilon, C.; Desvaux, Dominique; Saadoun, David; Barathon, Q.; Garrido, M del R; Audard, Vincent; Rémy, Philippe; Lang, Philippe; Cohen, José L.; Grimbert, Philippe

doi:10.1111/ajt.13304

Cited by 21 publications

(15 citation statements)

References 30 publications

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“…Indeed, all in vivo drug treatments reduced the susceptibility of CD4 + T‐cells to differentiate toward a pro‐inflammatory TH17 effector phenotype. These results are in line with the growing body of literature recognizing the involvement of effector TH17 cells in transplant rejection . We have noted substantial differences on the effects promoted by PI‐103 in vitro and in vivo , which may be attributed to the rapid plasma and tissue clearance exhibited by this compound .…”

Section: Discussionsupporting

confidence: 85%

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

et al. 2017

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The PI3K/mTOR signaling cascade is fundamental in T-cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T-cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T-cell activities. Substantial adverse effects in long-term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T-cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI-103 and PKI-587 inhibitors interfered IL-2-dependent responses in T-cells. However, in contrast to the inhibitory effects in non-Treg T-cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI-103, and PKI-587 targeted different signaling events and induced different metabolic patterns in primary T-cells. Similar to rapamycin, in vivo administration of PI-103 and PKI-587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T-cells and support their potential as a novel therapeutic option in transplantation.

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Section: Discussionsupporting

confidence: 85%

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

et al. 2017

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“…Clinical manifestations caused by Treg dysfunction observed in some autoimmune diseases are known to be insensitive to steroids. 44,45 Using graft biopsies, Matignon et al 46 performed a molecular analysis of the T cell immune response of patients with acute TCMR. IL-21 but not IL-17, RORgt, or T-bet was significantly higher in the patients who did not experience a successful reversal of acute TCMR after antirejection therapy, suggesting a potential role for IL-21 in steroid resistance.…”

Section: Discussionmentioning

confidence: 99%

Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection

Ville

Poirier

Branchereau

et al. 2016

JASN

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Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 (n=5), a selective pegylated Fab' antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid-resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell-specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro, FR104 controlled the proliferative response of human preexisting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.

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“…It combines major ischemia-induced cell stress, significant burst of free radicals, and intense inflammatory immune responses that lead to extensive cell injury, necrosis, and late interstitial fibrosis of the kidney allograft 1, 5 . Today, the increasing demand for renal allografts implies more frequent use of organs issued from extended criteria donors and this change leads to an increased risk of DGF 6, 7 . So far, there is no specific treatment of IRI and a better understanding of underlying mechanisms might lead to a better prevention of DGF and successful transplantations even with transplant from extended criteria donors.…”

Section: Introductionmentioning

confidence: 99%

Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury

Rossi

Thierry

Delbauve

et al. 2017

Sci Rep

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Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1M-KO), littermate (LT), and wild-type (WT) mice were subjected to renal IRI or sham procedures and sacrificed after 24 hours or 7 days. In comparison to LT, HO-1M-KO exhibited significant renal histological damage, pro-inflammatory responses and oxidative stress 24 hours after reperfusion. HO-1M-KO mice also displayed impaired tubular repair and increased renal fibrosis 7 days after IRI. In WT mice, HO-1 induction with hemin specifically upregulated HO-1 within the CD11b+ F4/80lo subset of the renal myeloid cells. Prior administration of hemin to renal IRI was associated with significant increase of the renal HO-1+ CD11b+ F4/80lo myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was abolished in HO-1M-KO mice. In conclusion, myeloid HO-1 appears as a critical protective pathway against renal IRI and could be an interesting therapeutic target in renal transplantation.

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

Cited by 21 publications

References 30 publications

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection

Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury

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