Karine Renaudin

Centre Hospitalier Universitaire de Nantes, Naoned, Pays de la Loire, France

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Publications (78)301.9 Total impact

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    ABSTRACT: We previously described that in a rat model of heart transplantation tolerance was dependent on CD8+CD45RClow Tregs that over-expressed fibrinogen-like protein 2 (FGL2)/fibroleukin. Little is known on the immunoregulatory properties of FGL2. Here we analyzed the transplantation tolerance mechanisms that are present in Lewis 1A rats treated with FGL2. Over-expression of FGL2 in vivo through adenovirus associated virus -mediated gene transfer without any further treatment resulted in inhibition of cardiac allograft rejection. Adoptive cell transfer of splenocytes from FGL2-treated rats with long-term graft survival (> 80 days) in animals that were transplanted with cardiac allografts inhibited acute and chronic organ rejection in a donor-specific and transferable tolerance manner, since iterative adoptive transfer up to a sixth consecutive recipient resulted in transplantation tolerance. Adoptive cell transfer also efficiently inhibited anti-donor antibody production. Analysis of all possible cell populations among splenocytes revealed that B lymphocytes were sufficient for this adoptive cell tolerance. These B cells were also capable of inhibiting the proliferation of CD4+ T cells in response to allogeneic stimuli. Moreover, gene transfer of FGL2 in B cell deficient rats did not prolong graft survival. Thus, this is the first description of FGL2 resulting in long-term allograft survival. Furthermore, allograft tolerance was transferable and B cells were the main cells responsible for this effect.
    PLoS ONE 03/2015; 10(3):e0119686. DOI:10.1371/journal.pone.0119686 · 3.53 Impact Factor
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    ABSTRACT: Galactosyl-transferase KO (GalT-KO) pigs represent a potential solution to xenograft rejection, particularly in the context of additional genetic modifications. We have performed life supporting kidney xenotransplantation into baboons utilizing GalT-KO pigs transgenic for human CD55/CD59/CD39/HT. Baboons received tacrolimus, mycophenolate mofetil, corticosteroids and recombinant human C1 inhibitor combined with cyclophosphamide or bortezomib with or without 2-3 plasma exchanges. One baboon received a control GalT-KO xenograft with the latter immunosuppression. All immunosuppressed baboons rejected the xenografts between days 9 and 15 with signs of acute humoral rejection, in contrast to untreated controls (n = 2) that lost their grafts on days 3 and 4. Immunofluorescence analyses showed deposition of IgM, C3, C5b-9 in rejected grafts, without C4d staining, indicating classical complement pathway blockade but alternate pathway activation. Moreover, rejected organs exhibited predominantly monocyte/macrophage infiltration with minimal lymphocyte representation. None of the recipients showed any signs of porcine endogenous retrovirus transmission but some showed evidence of porcine cytomegalovirus (PCMV) replication within the xenografts. Our work indicates that the addition of bortezomib and plasma exchange to the immunosuppressive regimen did not significantly prolong the survival of multi-transgenic GalT-KO renal xenografts. Non-Gal antibodies, the alternative complement pathway, innate mechanisms with monocyte activation and PCMV replication may have contributed to rejection. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
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    ABSTRACT: Selective targeting of CD28 might represent an effective immunomodulation strategy by preventing T cell costimulation, while favoring coinhibition since inhibitory signals transmitted through CTLA-4; PD-L1 and B7 would not be affected. We previously showed in vitro and in vivo that anti-CD28 antagonists suppress effector T cells while enhancing regulatory T cell (Treg) suppression and immune tolerance. Here, we evaluate FR104, a novel antagonist pegylated anti-CD28 Fab' antibody fragment, in nonhuman primate renal allotransplantation. FR104, in association with low doses of tacrolimus or with rapamycin in a steroid-free therapy, prevents acute rejection and alloantibody development and prolongs allograft survival. However, when FR104 was associated with mycophenolate mofetil and steroids, half of the recipients rejected their grafts prematurely. Finally, we observed an accumulation of Helios-negative Tregs in the blood and within the graft after FR104 therapy, confirmed by Treg-specific demethylated region DNA analysis. In conclusion, FR104 reinforces immunosuppression in calcineurin inhibitor (CNI)-low or CNI-free protocols, without the need of steroids. Accumulation of intragraft Tregs suggested the promotion of immunoregulatory mechanisms. Selective CD28 antagonists might become an alternative CNI-sparing strategy to B7 antagonists for kidney transplant recipients.
    American Journal of Transplantation 12/2014; 15(1). DOI:10.1111/ajt.12964 · 6.19 Impact Factor
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    ABSTRACT: Donor-specific antibodies (DSA) are considered as reliable biomarkers for antibody-mediated rejection (ABMR) diagnosis. However, it is unclear whether DSA monitoring is necessary and could predict graft outcome after antirejection treatment.
    Transplantation 07/2014; 99(1). DOI:10.1097/TP.0000000000000285 · 3.78 Impact Factor
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    ABSTRACT: We report the case of a patient affected by a voluminous prostatic tumor for which the histological analysis conclude in a stromal tumor of uncertain malignant potential. This type of tumor is rare, but requires to be individualized to differentiate it from a benign prostatic hyperplasia or a sarcoma of the prostate. The therapeutic care must be made keeping in mind the risk of degeneration towards a malignant shape.
    Annales de Pathologie 06/2014; 34(3):233-6. DOI:10.1016/j.annpat.2014.03.008 · 0.29 Impact Factor
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    ABSTRACT: In a rat heart allograft model, preventing T cell costimulation with CD40Ig leads to indefinite allograft survival, which is mediated by the induction of CD8+CD45RClo regulatory T cells (CD8+CD40Ig Tregs) interacting with plasmacytoid dendritic cells (pDCs). The role of TCR-MHC-peptide interaction in regulating Treg activity remains a topic of debate. Here, we identified a donor MHC class II-derived peptide (Du51) that is recognized by TCR-biased CD8+CD40Ig Tregs and activating CD8+CD40Ig Tregs in both its phenotype and suppression of antidonor alloreactive T cell responses. We generated a labeled tetramer (MHC-I RT1.Aa/Du51) to localize and quantify Du51-specific T cells within rat cardiac allografts and spleen. RT1.Aa/Du51-specific CD8+CD40Ig Tregs were the most suppressive subset of the total Treg population, were essential for in vivo tolerance induction, and expressed a biased, restricted Vβ11-TCR repertoire in the spleen and the graft. Finally, we demonstrated that treatment of transplant recipients with the Du51 peptide resulted in indefinite prolongation of allograft survival. These results show that CD8+CD40Ig Tregs recognize a dominant donor antigen, resulting in TCR repertoire alterations in the graft and periphery. Furthermore, this allopeptide has strong therapeutic activity and highlights the importance of TCR-peptide-MHC interaction for Treg generation and function.
    The Journal of clinical investigation 05/2014; 124(6). DOI:10.1172/JCI71533 · 13.77 Impact Factor
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    ABSTRACT: We report the case of a patient affected by a voluminous prostatic tumor for which the histological analysis conclude in a stromal tumor of uncertain malignant potential. This type of tumor is rare, but requires to be individualized to differentiate it from a benign prostatic hyperplasia or a sarcoma of the prostate. The therapeutic care must be made keeping in mind the risk of degeneration towards a malignant shape.
    Annales de Pathologie 01/2014; · 0.29 Impact Factor
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    ABSTRACT: GPB are often performed in PRT to detect subclinical acute rejection or IF/TA. Reducing immunosuppression side effects without increasing rejection is a major concern in PRT. We report the results of GPB in children transplanted with a steroid-sparing protocol adapted to immunological risk. Children under 18 yr who received a renal transplantation between April 1, 2009 and May 31, 2012 were included. Immunosuppression consisted of an antibody induction therapy, tacrolimus, and MMF for all recipients. CSs were administered to children under five yr old, or receiving a second allograft. Twenty-eight children were included, 50% were CSs free. GPB were performed between three and six months. IF/TA was documented in seven biopsies; four of these seven children were CS free. One child, with CSs, presented a borderline rejection, and another child, steroid free, with significant inflammatory interstitial infiltrate, considered as a subclinical rejection, was treated with CSs pulses. The median eGFR was stable (74, 67.5, and 82 mL/min/1.73 m² at, respectively, seven days, three months, and one yr). Patient and graft survival were 100%. These results have to be confirmed in a larger cohort, with long-term follow-up.
    Pediatric Transplantation 12/2013; 18(2). DOI:10.1111/petr.12197 · 1.63 Impact Factor
  • Néphrologie & Thérapeutique 09/2013; 9(5):270. DOI:10.1016/j.nephro.2013.07.165 · 0.55 Impact Factor
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    ABSTRACT: The angiotensin II type 1 receptor (AT1 R) is an emerging target of functional non-HLA antibodies (Ab). We examined the potential of determining the degree of presensitization against AT1 R as a risk factor for graft survival and acute rejection (AR). The study included 599 kidney recipients between 1998 and 2007. Serum samples were analyzed in a blinded fashion for anti-AT1 R antibodies (AT1 R-Abs) using a quantitative solid-phase assay. A threshold of AT1 R-Ab levels was statistically determined at 10 U based on the time to graft failure. An extended Cox model determined risk factors for occurrence of graft failure and a first AR episode. AT1 R-Abs >10 U were detected in 283 patients (47.2%) before transplantation. Patients who had a level of AT1 R-Abs >10 U had a 2.6-fold higher risk of graft failure from 3 years posttransplantation onwards (p = 0.0005) and a 1.9-fold higher risk of experiencing an AR episode within the first 4 months of transplantation (p = 0.0393). Antibody-mediated rejection (AMR) accounted for 1/3 of AR, whereby 71.4% of them were associated with >10 U of pretransplant AT1 R-Abs. Pretransplant anti-AT1 R-Abs are an independent risk factor for long-term graft loss in association with a higher risk of early AR episodes.
    American Journal of Transplantation 08/2013; 13(10). DOI:10.1111/ajt.12397 · 6.19 Impact Factor
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    ABSTRACT: In renal transplantation, the unresponsiveness of patients undergoing chronic antibody mediated rejection (CAMR) to classical treatment stress on the need for accurate biomarkers to improve its diagnosis. We aim to determine whether microRNA expression patterns may be associated with a diagnosis of CAMR. We performed expression profiling of miRNAs in peripheral blood mononuclear cells (PBMC) of kidney transplant recipients with CAMR or stable graft function. Among 257 expressed miRNAs, 10 miRNAs associated with CAMR were selected. Among them, miR-142-5p was increased in PBMC and biopsies of patients with CAMR as well as in a rodent model of CAMR. The lack of modulation of miR-142-5p in PBMC of patients with renal failure, suggests that its over-expression in CAMR was associated with immunological disorders rather than renal dysfunction. A ROC curve analysis performed on independent samples showed that miR-142-5p is a potential biomarker of CAMR allowing a very good discrimination of the patients with CAMR (AUC = 0.74; p = 0.0056). Moreover, its expression was decreased in PHA-activated blood cells and was not modulated in PBMC from patients with acute rejection, excluding a non-specific T cell activation expression. The absence of modulation of this miRNA in immunosuppressed patients suggests that its expression was not influenced by treatment. Finally, the analysis of miR-142-5p predicted targets under-expressed in CAMR PBMC in a published microarray dataset revealed an enrichment of immune-related genes. Altogether, these data suggest that miR-142-5p could be used as a biomarker in CAMR and these finding may improve our understanding of chronic rejection mechanisms.
    PLoS ONE 04/2013; 8(4):e60702. DOI:10.1371/journal.pone.0060702 · 3.53 Impact Factor
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    ABSTRACT: OBJECTIVES: The objective of our study was to analyze the diagnostic performance of (18) F-fluorodeoxyglucose positron emission tomography-computed tomography for lymph node staging in patients with bladder cancer before radical cystectomy and to compare it with that of computed tomography. METHODS: A total of 52 patients operated on between 2005 and 2010 were prospectively included in this prospective, mono-institutional, open, non-randomized pilot study. Patients who had received neoadjuvant chemotherapy or radiotherapy were excluded. (18) F-fluorodeoxyglucose positron emission tomography-computed tomography in addition to computed tomography was carried out for lymph node staging of bladder cancer before radical cystectomy. Lymph node dissection during radical cystectomy was carried out. Findings from (18) F-fluorodeoxyglucose positron emission tomography-computed tomography and computed tomography were compared with the results of definitive histological examination of the lymph node dissection. The diagnostic performance of the two imaging modalities was assessed and compared. RESULTS: The mean number of lymph nodes removed during lymph node dissection was 16.5 ± 10.9. Lymph node metastasis was confirmed on histological examination in 22 cases (42.3%). This had been suspected in five cases (9.6%) on computed tomography and in 12 cases (23.1%) on (18) F-fluorodeoxyglucose positron emission tomography-computed tomography. Sensitivity, specificity, positive predictive value, negative predictive value, relative risk and accuracy were 9.1%, 90%, 40%, 57.4%, 0.91 and 55.7%, respectively, for computed tomography, and 36.4%, 86.7%, 66.7%, 65%, 2.72, 65.4%, respectively, for (18) F-fluorodeoxyglucose positron emission tomography-computed tomography. CONCLUSIONS: (18) F-fluorodeoxyglucose positron emission tomography-computed tomography is more reliable than computed tomography for preoperative lymph node staging in patients with invasive bladder carcinoma undergoing radical cystectomy.
    International Journal of Urology 12/2012; DOI:10.1111/iju.12045 · 1.80 Impact Factor
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    ABSTRACT: BACKGROUND: Blockade of costimulation signaling required for immune response, such as CD40/CD40L and CD28/B7, is a reasonable strategy to prevent rejection and in defined combinations may allow donor specific tolerance. Indeed, in rodents, costimulation blockade with CD28/B7 antagonists or with CD40Ig was able to induce regulatory T cells and transplant tolerance whereas in primates, anti-CD40 antibodies, anti-CD40L antibodies or CTLA4Ig, used as monotherapy, significantly delayed graft rejection. METHODS: Using an adeno-associated virus (AAV) vector mediated gene transfer of a human CD40Ig fusion protein (hCD40Ig) in primates, we evaluated the capacity of this costimulation blockade molecule interfering with CD40/CD40L signaling in prolonging kidney transplants in cynomolgus monkeys. RESULTS: This gene transfer strategy allowed for maintaining a plateau of hCD40Ig production within two months and avoided a high-scale production phase of this molecule. Although the hCD40Ig was able to bind efficiently to human and macaque CD40L and high (>200μg/ml) transgene expression was obtained, no effect on graft survival was observed. In addition, there was no inhibition of humoral response to vaccination. In vitro, hCD40Ig strongly increased mixed lymphocyte reaction, and when compared to the anti-CD40L antibody h5C8, was not as potent to induce complement-dependent cytotoxicity. CONCLUSION: These data suggest that CD40/CD40L blockade using a non-depleting CD40Ig fusion protein, a therapeutic strategy that showed efficacy in rodents, is not able to modulate the immune response in primates. These data highlight important biological differences between rodent and primate models to evaluate therapeutic strategies at the preclinical level.
    Transplant Immunology 10/2012; 27(4). DOI:10.1016/j.trim.2012.10.004 · 1.83 Impact Factor
  • 10/2012; 129(4):A25. DOI:10.1016/j.aforl.2012.07.063
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    ABSTRACT: Prostatic Stromal Tumors of Uncertain Malignant Potential (STUMP) are rare tumor of the prostate of mesenchymal origin, accounting, with sarcoma for 0.1–0.2% of all malignant prostatic tumours. They however require to be individualized, to differentiate it from a benign prostatic hyperplasia or a sarcoma of the prostate. The therapeutic management should be made keeping in mind the risk of degeneration towards a malignant shape. Although the appropriate treatment is unknown, radical prostatectomy seem to be the treatment of reference, especially for young patient or for extensive lesion.
    Progrès en Urologie 10/2012; 22(12):688–691. DOI:10.1016/j.purol.2012.06.004 · 0.77 Impact Factor
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    ABSTRACT: We report here on a European cohort of 27 kidney transplant recipients displaying operational tolerance, compared to two cohorts of matched kidney transplant recipients under immunosuppression and patients who stopped immunosuppressive drugs and presented with rejection. We report that a lower proportion of operationally tolerant patients received induction therapy (52% without induction therapy vs. 78.3%[p = 0.0455] and 96.7%[p = 0.0001], respectively), a difference likely due to the higher proportion (18.5%) of HLA matched recipients in the tolerant cohort. These patients were also significantly older at the time of transplantation (p = 0.0211) and immunosuppression withdrawal (p = 0.0002) than recipients who rejected their graft after weaning. Finally, these patients were at lower risk of infectious disease. Among the 27 patients defined as operationally tolerant at the time of inclusion, 19 still display stable graft function (mean 9 ± 4 years after transplantation) whereas 30% presented slow deterioration of graft function. Six of these patients tested positive for pre-graft anti-HLA antibodies. Biopsy histology studies revealed an active immunologically driven mechanism for half of them, associated with DSA in the absence of C4d. This study suggests that operational tolerance can persist as a robust phenomenon, although eventual graft loss does occur in some patients, particularly in the setting of donor-specific alloantibody.
    American Journal of Transplantation 09/2012; 12(12). DOI:10.1111/j.1600-6143.2012.04249.x · 6.19 Impact Factor
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    ABSTRACT: The clinical merit of surveillance kidney graft biopsies remains controversial. A retrospective, multicenter analysis evaluated 12-month surveillance biopsies (SB, 154 patients) versus no SB (NSB, 138 patients (11 with diagnostic biopsy)) in patients >18 months posttransplant with estimated GFR (eGFR) ≥30 mL/min. The primary objective was to describe renal function at 18 months post-transplant in patients with or without SB at month 12. Globally, most recipients in both cohorts were at low immunological risk (<10% of patients with PRA ≥30%). The immunosuppressive regimen remained unchanged following more than half of SB that exhibited chronic lesions (18/33, 54.5%). Mean (SD) eGFR at month 18 (primary endpoint) was 56 (19) mL/min/1.73 m² with SB and 54 (15) mL/min/1.73 m² with NSB (P = 0.48). In the SB group, slight nonspecific changes were observed in 51 cases, rejection (acute or chronic) in 6 cases, CNI-related toxicity in 15 cases, recurrence of initial disease in two cases, and interstitial fibrosis/tubular atrophy (IF/TA) in 83 cases (71.6%), of which 35 cases (30.2%) were grade II/III lesions. eGFR <50 mL/min/1.73 m² at month 6 predicted IF/TA grade II or III (OR 3.85, 95% CI 1.64, 9.05, P < 0.002). SB at 12 months posttransplant did not prompt significant modification of immunosuppression, and no renal benefit was observed.
    Journal of Transplantation 09/2012; 2012:781263. DOI:10.1155/2012/781263
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    ABSTRACT: The Weiss score is the reference method to distinguish between a benign and a malignant adrenocortical tumor (ACT). A program was initiated to improve the reproducibility of the pathologic diagnosis of ACTs in France through the National INCa-COMETE Network. Twelve pathologists from all Reference Centers of the Network analyzed 50 selected ACTs using a web-based virtual microscopy approach in a blind design, allowing to determine the intraobserver and interobserver reproducibilities of the Weiss system. All ACTs were read twice in random order before and after a coaching meeting organized to harmonize and improve analyses and create an online tutorial. The validity of the virtual approach was first established by comparing the 2 consensuses (virtual and microscopic) obtained for each tumor by 3 pathologists who performed the 2 approaches in a blinded manner. For the "dichotomized Weiss score" (separating malignant ≥3 from benign ≤2 tumors) interobserver reproducibility was "substantial" at the first "virtual" reading (κ = 0.70) and increased at the second "virtual" reading (κ = 0.75). In parallel, 7 of the 9 items of the Weiss system showed improvement. The diagnostic accuracy of the observers as a group, using the modal group score approach, showed an improved sensitivity from 86% to 95% for the diagnosis of malignant ACTs. We show the validity of the virtual microscopy approach and that the program improved the practice of the Weiss system reading and therefore the diagnosis of ACT. This tool can now be extended for other research and/or routine purposes in this rare cancer.
    The American journal of surgical pathology 08/2012; 36(8):1194-201. DOI:10.1097/PAS.0b013e31825a6308 · 4.59 Impact Factor
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    ABSTRACT: Galactosyl-transferase knockout (GT-KO) pigs represent the latest major progress to reduce immune reactions in xenotransplantation. However, their organs are still subject to rapid humoral rejection involving complement activation requiring the ongoing development of further genetic modifications in the pig. In a pig-to-baboon renal transplantation setting, we have used donor pigs that are not only GT-KO, but also transgenic for human CD55 (hCD55), hCD59, hCD39, and fucosyl-transferase (hHT). We studied kidney xenograft survival, physiological and immunologic parameters, xenogeneic rejection characteristics, as well as viral transmission aspects among two groups of baboons: control animals (n = 2), versus those (n = 4) treated with a cocktail of cyclophosphamide, tacrolimus, mycophenolate mofetil, steroids, and a recombinant human C1 inhibitor. Whereas control animals showed clear acute humoral rejection at around day 4, the treated animals showed moderately improved graft survival with rejection at around 2 weeks posttransplantation. Biopsies showed signs of acute vascular rejection (interstitial hemorrhage, glomerular thrombi, and acute tubular necrosis) as well as immunoglobulin (Ig)M and complement deposition in the glomerular and peritubular capillaries. The low level of preformed non-Gal-α1.3Gal IgM detected prior to transplantation increased at 6 days posttransplantation, whereas induced IgG appeared after day 6. No porcine endogenous retrovirus (PERV) transmission was detected in any transplanted baboon. Thus, surprisingly, organs from the GT-KO, hCD55, hCD59, hCD39, and hHT transgenic donors did not appear to convey significant protection against baboon anti-pig antibodies and complement activation, which obviously continue to be significant factors under a suboptimal immunosuppression regimen. The association, timing, and doses of immunosuppressive drugs remain critical. They will have to be optimized to achieve longer graft survivals.
    Transplantation Proceedings 11/2011; 43(9):3426-30. DOI:10.1016/j.transproceed.2011.09.024 · 0.95 Impact Factor
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    ABSTRACT: The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.
    American Journal of Transplantation 08/2011; 11(9):1792-802. DOI:10.1111/j.1600-6143.2011.03670.x · 6.19 Impact Factor

Publication Stats

2k Citations
301.90 Total Impact Points

Institutions

  • 2002–2015
    • Centre Hospitalier Universitaire de Nantes
      • • Institut de transplantation urologie-néphrologie
      • • Service d'anatomie pathologique
      Naoned, Pays de la Loire, France
  • 2007–2014
    • Hôtel-Dieu de Paris – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2007–2012
    • University of Nantes
      • Faculté de Médecine
      Naoned, Pays de la Loire, France
  • 2002–2011
    • French Institute of Health and Medical Research
      • Center of Research in Transplantation and Immunology CRTI
      Lutetia Parisorum, Île-de-France, France
  • 2004
    • Institut de Recherche en Communications et Cybernétique de Nantes
      Naoned, Pays de la Loire, France