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51. TCF7L2 polymorphism associates with new-onset diabetes after transplantation.

Author

Ghisdal, Lidia, Baron, Christophe, Le Meur, Yannick, Lionet, Arnaud, Halimi, Jean-Michel, Rerolle, Jean-Philippe, Glowacki, François, Lebranchu, Yvon, Drouet, Mireille, Noel, Christian, El Housni, Hakim, Cochaux, Pascale, Wissing, Karl Martin, Abramowicz, Daniel, Abramowicz, Marc, Ghisdal, Lidia, Baron, Christophe, Le Meur, Yannick, Lionet, Arnaud, Halimi, Jean-Michel, Rerolle, Jean-Philippe, Glowacki, François, Lebranchu, Yvon, Drouet, Mireille, Noel, Christian, El Housni, Hakim, Cochaux, Pascale, Wissing, Karl Martin, Abramowicz, Daniel, and Abramowicz, Marc

Abstract

New-onset diabetes after transplantation (NODAT) is a serious and frequent complication in transplant recipients. Whether NODAT shares the same susceptibility genes as type 2 diabetes is unknown. In this multicenter study, we genotyped 1076 white patients without diabetes at transplantation for 11 polymorphisms that associate with type 2 diabetes. We defined NODAT as a fasting plasma glucose > or =126 mg/dl on at least two occasions or de novo hypoglycemic therapy. We compared clinical and genetic factors between patients who developed NODAT within 6 mo of transplantation (n = 118; incidence 11%) and patients without diabetes (n = 958). In multivariate analysis, NODAT significantly associated with the following characteristics: TCF7L2 polymorphism (odds ratio [OR] 1.60 per each T allele; P = 0.002), age (OR 1.03 per year; P < 0.001), body mass index at transplantation (OR 1.09 per unit; P < 0.001), tacrolimus use (OR 2.26; P < 0.001), and the occurrence of a corticoid-treated acute rejection episode (OR 2.78; P < 0.001). In summary, our data show that the TCF7L2 rs7903146 polymorphism, a known risk factor for type 2 diabetes in the general population, also associates with NODAT., Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2009

53. Pharmacokinetic and pharmacodynamic studies of two different rabbit antithymocyte globulin dosing regimens: Results of a randomized trial

Author

Büchler, Matthias, primary, Longuet, Hélène, additional, Lemoine, Roxane, additional, Herr, Florence, additional, Gatault, Philippe, additional, Thibault, Gilles, additional, Ternant, David, additional, Foulon, Christine, additional, Pilorge, Bernadette, additional, Lemay, Djamila, additional, Sung, Crystal, additional, Halimi, Jean-Michel, additional, Baron, Christophe, additional, and Lebranchu, Yvon, additional

Published
2013
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54. A role for CD2 antibodies (BTI-322 and its humanized form) in the in vivo elimination of human T lymphocytes infiltrating an allogeneic human skin graft in SCID mice: an Fcgamma receptor-related mechanism involving co-injected human NK cells.

Author

UCL - MD/CHIR - Département de chirurgie, Snanoudj, Renaud, Rouleau, Matthieu, Bidère, Nicolas, Carmona, Sylvie, Baron, Christophe, Latinne, Dominique, Bazin, Hervé, Charpentier, Bernard, Senik, Anna, UCL - MD/CHIR - Département de chirurgie, Snanoudj, Renaud, Rouleau, Matthieu, Bidère, Nicolas, Carmona, Sylvie, Baron, Christophe, Latinne, Dominique, Bazin, Hervé, Charpentier, Bernard, and Senik, Anna

Abstract

BACKGROUND: Pilot clinical studies have shown that the rat anti-human-CD2 monoclonal antibody, LoCD2a/BTI-322, can efficiently prevent and treat acute kidney rejection. However, the in vivo mechanism by which it prevents allograft rejection has not been studied. BTI-322 and its humanized form have been shown to mediate in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) against CD2 cells through the activation of monocytes or natural killer (NK) cells. METHODS: Human fetal skin samples were grafted into severe combined immunodeficient/nonobese diabetic mice. Five weeks later (day 0), the mice were injected with human allogeneic peripheral blood lymphocytes (PBL). Either on day 0 or on day 14, mice were treated with BTI-322, hu-BTI-322, or their F(ab')2 fragments. Peripheral blood mononuclear cells (PBMC) thoroughly devoid of NK cells were also assayed. RESULTS: After injection of PBL, the human skins became heavily infiltrated with activated human T lymphocytes, resulting in dermal microvascular injuries indicative of graft rejection. Early treatment with BTI-322 and hu-BTI-322 prevented all these events. These CD2 antibodies rapidly eliminated human T lymphocytes that had already infiltrated the grafts, with no evidence of recirculation toward the spleen. Their F(ab')2 fragments were, in contrast, ineffective. Elimination of NK cells from injected PBMC prevented the curative effect exerted by whole CD2 antibodies. It also abrogated their cytotoxicity potential against CD2 cells in ADCC assays. CONCLUSION: F(ab')2 fragments of the CD2 antibodies could not prevent allograft rejection, whereas whole immunoglobulin G could, and human NK cells were required for the curative effect exerted by these antibodies. The results are consistent with an FcgammaR-dependent ADCC mechanism mediated in vivo by human NK cells.

Published
2004

57. TCF7L2 Polymorphism Associates with New-Onset Diabetes after Transplantation

Author

Ghisdal, Lidia, primary, Baron, Christophe, additional, Le Meur, Yannick, additional, Lionet, Arnaud, additional, Halimi, Jean-Michel, additional, Rerolle, Jean-Philippe, additional, Glowacki, François, additional, Lebranchu, Yvon, additional, Drouet, Mireille, additional, Noël, Christian, additional, El Housni, Hakim, additional, Cochaux, Pascale, additional, Wissing, Karl Martin, additional, Abramowicz, Daniel, additional, and Abramowicz, Marc, additional

Published
2009
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58. Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression

Author

UCL - Autre, Mourad, Georges, Garrigue, Valérie, Squifflet, Jean-Paul, Besse, Tatiana, Berthoux, François, Alamartine, Eric, Durand, Dominique, Rostaing, Lionel, Lang, Philippe, Baron, Christophe, Glotz, Denis, Antoine, Corinne, Vialtel, Paul, Romanet, Thierry, Lebranchu, Yvon, Al Najjar, Azmi, Hiesse, Christian, Potaux, Luc, Merville, Pierre, Touraine, Jean-Louis, Lefrancois, Nicole, Kessler, Michèle, Renoult, Edith, Pouteil-Noble, Claire, Cahen, Remi, Legendre, Christophe, Bedrossian, Jeanine, Le Pogamp, Patrick, Rivalan, Joseph, Olmer, Michel, Purgus, Raj, Mignon, Françoise, Viron, Béatrice, Charpentier, Bernard, UCL - Autre, Mourad, Georges, Garrigue, Valérie, Squifflet, Jean-Paul, Besse, Tatiana, Berthoux, François, Alamartine, Eric, Durand, Dominique, Rostaing, Lionel, Lang, Philippe, Baron, Christophe, Glotz, Denis, Antoine, Corinne, Vialtel, Paul, Romanet, Thierry, Lebranchu, Yvon, Al Najjar, Azmi, Hiesse, Christian, Potaux, Luc, Merville, Pierre, Touraine, Jean-Louis, Lefrancois, Nicole, Kessler, Michèle, Renoult, Edith, Pouteil-Noble, Claire, Cahen, Remi, Legendre, Christophe, Bedrossian, Jeanine, Le Pogamp, Patrick, Rivalan, Joseph, Olmer, Michel, Purgus, Raj, Mignon, Françoise, Viron, Béatrice, and Charpentier, Bernard

Abstract

Background. The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients. Methods. This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1-2 mg/kg per day. Results. At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P=0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P=0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P=0.009), leukopenia (37.3% vs. 9.5%, P<0.001), fever (25.2% vs. 10.1%, P=0.001), herpes simplex (17.9% vs. 5.7%, P=0.001), and thrombocytopenia (11.3% vs. 3.2%, P=0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction). Conclusion. Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV

Published
2001

61. Association Between a Polymorphism in the IL-12p40 Gene and Cytomegalovirus Reactivation After Kidney Transplantation

Author

Hoffmann, Thomas W., primary, Halimi, Jean-Michel, additional, Büchler, Mathias, additional, Velge-Roussel, Florence, additional, Goudeau, Alain, additional, Najjar, Azmi Al, additional, Boulanger, Marie-Denise, additional, Houssaini, Tarik Sqalli, additional, Marliere, Jean-Frédéric, additional, Lebranchu, Yvon, additional, and Baron, Christophe, additional

Published
2008
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66. A Role for CD2 Antibodies (BTI-322 and its Humanized Form) in the in vivo Elimination of Human T Lymphocytes Infiltrating an Allogeneic Human Skin Graft in SCID Mice: An Fcγ Receptor-Related Mechanism Involving Co-Injected Human NK Cells

Author

Snanoudj, Renaud, primary, Rouleau, Matthieu, additional, Bidère, Nicolas, additional, Carmona, Sylvie, additional, Baron, Christophe, additional, Latinne, Dominique, additional, Bazin, Hervé, additional, Charpentier, Bernard, additional, and Senik, Anna, additional

Published
2004
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68. LONG-TERM KIDNEY GRAFT SURVIVAL ACROSS A POSITIVE HISTORIC BUT NEGATIVE CURRENT SENSITIZED CROSS-MATCH1

Author

Baron, Christophe, primary, Pastural, Myriam, additional, Lang, Philippe, additional, Bentabet, Radia, additional, el Kassar, Nahed, additional, Seror, Th??r??se, additional, Dahmane, Djamel, additional, Desvaux, Dominique, additional, Chopin, Dominique, additional, Fruchaud, Ghislaine, additional, Remy, Philippe, additional, Grimbert, Philippe, additional, Lepage, Eric, additional, and Bierling, Philippe, additional

Published
2002
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70. INDUCTION VERSUS NONINDUCTION IN RENAL TRANSPLANT RECIPIENTS WITH TACROLIMUS-BASED IMMUNOSUPPRESSION1

Author

Mourad, Georges, primary, Garrigue, Val??rie, additional, Squifflet, Jean-Paul, additional, Besse, Tatiana, additional, Berthoux, Fran??ois, additional, Alamartine, Eric, additional, Durand, Dominique, additional, Rostaing, Lionel, additional, Lang, Philippe, additional, Baron, Christophe, additional, Glotz, Denis, additional, Antoine, Corinne, additional, Vialtel, Paul, additional, Romanet, Thierry, additional, Lebranchu, Yvon, additional, Al Najjar, Azmi, additional, Hiesse, Christian, additional, Potaux, Luc, additional, Merville, Pierre, additional, Touraine, Jean-Louis, additional, Lefrancois, Nicole, additional, Kessler, Mich??le, additional, Renoult, Edith, additional, Pouteil-Noble, Claire, additional, Cahen, Remi, additional, Legendre, Christophe, additional, Bedrossian, Jeanine, additional, Le Pogamp, Patrick, additional, Rivalan, Joseph, additional, Olmer, Michel, additional, Purgus, Raj, additional, Mignon, Fran??oise, additional, Viron, B??atrice, additional, and Charpentier, Bernard, additional

Published
2001
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73. Risk factors for impaired CD4+ T-cell reconstitution following rabbit antithymocyte globulin treatment in kidney transplantation.

Author

Longuet, Hélène, Sautenet, Bénédicte, Gatault, Philippe, Thibault, Gilles, Barbet, Christelle, Marliere, Jean-Frédérique, Halimi, Jean-Michel, Lebranchu, Yvon, Baron, Christophe, and Büchler, Matthias

Subjects
KIDNEY transplantation, LABORATORY rabbits, LYMPHOCYTES, MULTIVARIATE analysis, T cells
Abstract

To describe long-term CD4+ T-cell reconstitution after rabbit antithymocyte globulin ( rATG) treatment and identify predictive factors following kidney transplantation. A single-center retrospective study analyzed lymphocyte subsets in rATG-treated kidney transplant recipients (1986-2009). 589 patients were analyzed (maximum follow-up 21 years). A comparator group ( n = 298) received an anti-IL-2 receptor monoclonal antibody. CD4+ T-cell lymphopenia (<200/mm3) was present in 48.5%, 9.2%, 6.7%,2.0%, and 0% of patients at one, three, five, 10, and 20 years post-transplant, respectively. CD4+ T-cell count increased during the first 10 years but remained below the pretransplant count even after 20 years. At 1, 3, and 6 months post-transplant, mean CD4+ T-cell count was significantly lower in patients with CD4+ T-cell lymphopenia at 12 months versus patients without lymphopenia. On multivariate analyses, significant independent predictors for long-term impaired CD4 T-cell reconstitution were recipient age, pretransplant CD4+ T-cell count, 12-month CD4+ T-cell count, and tacrolimus or MMF therapy. Recipient age >40 years was identified as a cutoff point. CD4+ T-cell reconstitution following rATG treatment remains impaired even after 21 years. Most risk factors for long-term impaired CD4+ T-cell reconstitution may be evaluated pretransplant or are modifiable post-transplant. [ABSTRACT FROM AUTHOR]

Published
2014
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79. INDUCTION VERSUS NONINDUCTION IN RENAL TRANSPLANT RECIPIENTS WITH TACROLIMUS-BASED IMMUNOSUPPRESSION1.

Author

Mourad, Georges, Garrigue, Valérie, Squifflet, Jean-Paul, Besse, Tatiana, Berthoux, François, Alamartine, Eric, Durand, Dominique, Rostaing, Lionel, Lang, Philippe, Baron, Christophe, Glotz, Denis, Antoine, Corinne, Vialtel, Paul, Romanet, Thierry, Lebranchu, Yvon, Al Najjar, Azmi, Hiesse, Christian, Potaux, Luc, Merville, Pierre, and Touraine, Jean-Louis

Published
2001
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80. Induction of human CD4+regulatory T cells by mycophenolic acid‐treated dendritic cells

Author

Lagaraine, Christine, Lemoine, Roxane, Baron, Christophe, Nivet, Hubert, Velge‐Roussel, Florence, and Lebranchu, Yvon

Abstract

Depending on their degree of maturation, costimulatory molecule expression, and cytokine secretion, dendritic cells (DC) can induce immunity or tolerance. DC treated with mycophenolic acid during their maturation (MPA‐DC) have a regulatory phenotype and may therefore provide a new approach to induce allograft tolerance. Purified CD4+T cells stimulated in a human in vitro model of mixed culture by allogeneic MPA‐DC displayed much weaker proliferation than T cells activated by mature DC and were anergic. This hyporesponsiveness was alloantigen‐specific. Interestingly, T cells stimulated by MPA‐DC during long‐term coculture in four 7‐day cycles displayed potent, suppressive activity, as revealed by marked inhibition of the proliferation of naive and preactivated control T cells. These regulatory T cells (Tregs) appeared to have antigen specificity and were contact‐dependent. Tregs induced by MPA‐DC were CD25+glucocorticoid‐induced TNFR+CTLA‐4+CD95+, secreted IL‐5 and large amounts of IL‐10 and TGF‐β, and displayed enhanced forkhead box p3 expression. These results obtained in vitro demonstrate that human MPA‐DC can induce allospecific Tregs that may be exploited in cell therapy to induce allograft tolerance.

Published
2008
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81. Acute renal allograft rejections with major interstitial oedema and plasma cell-rich infiltrates: high gamma-interferon expression and poor clinical outcome.

Author

Desvaux, Dominique, Le Gouvello, Sabine, Pastural, Myriam, Abtahi, Mahdi, Suberbielle, Caroline, Boeri, Nicole, Rémy, Philippe, Salomon, Laurent, Lang, Philippe, and Baron, Christophe

Abstract

Acute rejections are scored according to three main criteria: vasculitis, tubulitis and interstitial infiltration as defined in the Banff classification. Typically, B cells account for <8% of the infiltrates and oedema is limited. The clinical significance of severe interstitial oedema and plasma cell-rich infiltrates (OPcR) are still a matter of debate.

Published
2004
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83. Pharmacokinetic and pharmacodynamic studies of two different rabbit antithymocyte globulin dosing regimens: Results of a randomized trial.

Author

Büchle, Matthias, Longue, Hélène, Lemoine, Roxane, Herrc, Florence, Gatault, Philippe, Thibault, Gilles, Ternant, David, Foulon, Christine, Pilorge, Bernadette, Lemay, Djamila, Sung, Crystal, Halimi, Jean-Michel, Baron, Christophe, and Lebranchu, Yvon

Subjects
*KIDNEY transplantation, *PHARMACOKINETICS, *PHARMACODYNAMICS, *LABORATORY rabbits, *THYMOCYTES, *GLOBULINS, *DRUG dosage, *CLINICAL trials
Abstract

Rabbit antithymocyte globulin (rATG; Thymoglobulin®) is currently used to prevent acute rejection in kidney transplantation. The dose and regimen of rATG have not been optimized. Moreover, the impact of different treatment regimens on T-cell phenotype reconstitution remains unknown. We conducted a prospective randomized study of 17 renal transplant patients to determine the pharmacokinetics of total and active (bound to human cells) rATG and T-cell phenotype reconstitution after rATG administration. Patients received rATG at a total dose of 6 mg/kg, administered either as 1.5 mg/kg/day on days 0-3 (Group 1, n = 8) or 3 mg/kg on days 0 and 3 (Group 2, n = 9). All patients received tacrolimus, mycophenolate mofetil and steroids. Blood samples were assayed for total rATG by enzyme linked immunosorbent assay and active tATG by flow cytometry. Maximum concentrations and terminal half-lives were similar between the two groups but at month 3 Group 1 had significantly lower values for total rATG (concentration was 6.2 ± 1.1 ug/mL versus 10.2 ± 2.9 ug/mL in Group 2, p = 0.027) and total rATG dose-normalized AUC (374 ± 83 day g/mL versus 508 ± 149 day g/mL in Group 2, p = 0.046). Time to sub-therapeutic levels (<1 µg/mL) of active rATG was significantly shorter in Group 1 (18.75 ± 6.9 days versus 20 ± 7.5 days in Group 2, p < 0.001). rATG induced significant depletion followed by slow reconstitution of CD3+, CD4+ and CD8+ cells, with no marked differences between groups. B-ceII count was unaffected, whereas CD3~CD56+ NK-cell depletion was observed in both groups. rATG induced a significant decrease in the proportion of naive CD4+ T-cells, which plateaued after month 1 in Group 1 and after month 6 in Group 2. The proportion of central memory CD4+ T-cells increased to a similar extent in both groups (Group 1:38 ± 18% at baseline, 74 ± 23% at one year, p = 0.009; Group 2:32 ± 14% at baseline, 65 ± 14% at one year, p = 0.001 ). In conclusion, our results suggest that the dosing regimen for rATG induction influences pharmacokinetic parameters without affecting the quality of immune reconstitution. [ABSTRACT FROM AUTHOR]

Published
2013
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84. The Voltage-Gated Sodium Channel Beta4 Subunit Maintains Epithelial Phenotype in Mammary Cells.

Author

Doray A, Lemoine R, Severin M, Chadet S, Lopez-Charcas O, Héraud A, Baron C, Besson P, Monteil A, Pedersen SF, and Roger S

Subjects
Animals, Cell Line, Cell Polarity, Down-Regulation, Epithelial Cells cytology, Female, Humans, Mesoderm metabolism, Phenotype, Proteolysis, beta Catenin metabolism, Epithelial Cells metabolism, Mammary Glands, Animal cytology, Protein Subunits metabolism, Voltage-Gated Sodium Channel beta-4 Subunit metabolism
Abstract

The SCN4B gene, coding for the Na V β4 subunit of voltage-gated sodium channels, was recently found to be expressed in normal epithelial cells and down-regulated in several cancers. However, its function in normal epithelial cells has not been characterized. In this study, we demonstrated that reducing Na V β4 expression in MCF10A non-cancer mammary epithelial cells generated important morphological changes observed both in two-dimensional cultures and in three-dimensional cysts. Most notably, the loss of Na V β4 induced a complete loss of epithelial organisation in cysts and increased proteolytic activity towards the extracellular matrix. Loss of epithelial morphology was associated with an increased degradation of β-catenin, reduced E-cadherin expression and induction of mesenchymal markers N-cadherin, vimentin, and α-SMA expression. Overall, our results suggest that Navβ4 may participate in the maintenance of the epithelial phenotype in mammary cells and that its downregulation might be a determining step in early carcinogenesis.

Published
2021
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85. The association between renal resistive index and premature mortality after kidney transplantation is modified by pre-transplant diabetes status: a cohort study.

Author

de Freminville JB, Vernier LM, Roumy J, Patat F, Gatault P, Sautenet B, Bailly E, Chevallier E, Barbet C, Longuet H, Merieau E, Baron C, Buchler M, and Halimi JM

Subjects
Blood Pressure, Female, Graft Rejection etiology, Graft Rejection pathology, Humans, Male, Middle Aged, Prognosis, Retrospective Studies, Survival Rate, Tissue Donors, Transplant Recipients, Diabetes Mellitus physiopathology, Graft Rejection mortality, Kidney physiopathology, Kidney Transplantation adverse effects, Mortality, Premature trends
Abstract

Background: Renal resistive index (RI) predicts mortality in renal transplant recipients, but we do not know whether this is true in diabetic patients. The objective of this study was to analyse the long-term predictive value of RI for death with a functioning graft (DWFG) in renal transplant recipients with or without pre-transplant diabetes., Methods: We conducted a retrospective study in 1800 renal transplant recipients between 1985 and 2017 who were followed for up to 30 years (total observation period: 14 202 patient years). Donor and recipient characteristics at time of transplantation and at 3 months were reviewed. The long-term predictive value of RI for DWFG and the age-RI and arterial pressure-RI relationships were assessed., Results: A total of 284/1800 (15.7%) patients had diabetes mellitus before transplantation. RI was <0.75 in 1327/1800 patients (73.7%). High RI was associated with a higher risk of DWFG in non-diabetic patients [hazard ratio (HR) = 3.39, 95% confidence interval 2.50-4.61; P < 0.001], but not in patients with pre-transplant diabetes (HR = 1.25, 0.70-2.19; P = 0.39), even after multiple adjustments. There was no interaction between diabetes and age. In contrast, there was an interaction between RI and pulse pressure., Conclusion: Our study indicates that RI is not a predictor of DWFG in diabetic renal transplant recipients, in contrast to non-diabetic recipients. These findings could be due to a different age-RI or pulse pressure-RI relationship., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Published
2020
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