Publications by authors named "Yvon Lebranchu"

89 Publications

Response to plasma exchange and graft survival in recurrent focal and segmental glomerulosclerosis after transplantation: does the time of recurrence matter? A retrospective study.

Transpl Int 2021 Feb 31;34(2):302-312. Epub 2020 Dec 31.

Department of Nephrology - Hypertension, Dialysis, Transplantation, CHRU, Tours, France.

Recurrence of primary focal and segmental glomerulosclerosis following kidney transplantation (rFSGS) is a frequent and severe disease. We studied the time to recurrence of FSGS and its impact on the response to plasma exchange (PE) and graft survival. Between 1990 and 2013, 2730 kidney transplants were performed, including 52 patients with a primary diagnosis of FSGS. Of these patients with primary FSGS, 34 (67%) developed rFSGS. We retrospectively divided these patients into two groups depending on the time to recurrence: early (up to three months after transplantation, n = 26) or late (more than three months after transplantation, n = 8). Survival did not significantly differ between the two groups. In cases of late recurrence, PE was started later and was performed less frequently, and remission was achieved after more PE sessions and longer PE treatment than for the early group (P = 0.01). In early recurrence, resistance to PE at 40 days was associated with no long-term response to PE. PE should be performed as soon as possible after rFSGS. Patients with late rFSGS need to be offered the same treatment regime as those with early rFSGS.
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http://dx.doi.org/10.1111/tri.13796DOI Listing
February 2021

A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

Authors:
Hélène Coignard-Biehler Nizar Mahlaoui Benoit Pilmis Vincent Barlogis Pauline Brosselin Nathalie De Vergnes Marianne Debré Marion Malphettes Pierre Frange Emilie Catherinot Isabelle Pellier Isabelle Durieu Antoinette Perlat Bruno Royer Alain Le Quellec Eric Jeziorski Alain Fischer Olivier Lortholary Laurent Aaron Daniel Adoue Claire Aguilar Nathalie Aladjidi Alexandre Alcais Zahir Amoura Philippe Arlet Corinne Armari-Alla Brigitte Bader-Meunier Sophie Bayart Yves Bertrand Boris Bienvenu Stéphane Blanche Damien Bodet Bernard Bonnotte Raphaël Borie Patrick Boutard Claire Briandet Jean-Paul Brion Jacques Brouard Sarah Cohen-Beaussant Laurence Costes Louis-Jean Couderc Pierre Cougoul Virginie Courteille Geneviève de Saint Basile Catherine Devoldere Anne Deville Jean Donadieu Eric Dore Fabienne Dulieu Christine Edan Natacha Entz-Werle Claire Fieschi Amandine Forestier Fanny Fouyssac Vincent Gajdos Lionel Galicier Virginie Gandemer Martine Gardembas Catherine Gaud Gaelle Guillerm Eric Hachulla Mohamed Hamidou Olivier Hermine Cyrille Hoarau Sébastien Humbert Arnaud Jaccard Serge Jacquot Jean-Philippe Jais Roland Jaussaud Pierre-Yves Jeandel Kamila Kebaili Anne-Sophie Korganow Olivier Lambotte Fanny Lanternier Claire Larroche Anne-Sophie Lascaux Emmanuelle Le Moigne Vincent Le Moing Yvon Lebranchu Marc Lecuit Guillaume Lefevre Richard Lemal Valérie Li Thiao Te Aude Marie-Cardine Nicolas Martin Silva Agathe Masseau Christian Massot Françoise Mazingue Etienne Merlin Gérard Michel Frédéric Millot Béatrice Monlibert Fabrice Monpoux Despina Moshous Luc Mouthon Martine Munzer Bénédicte Neven Raphaëlle Nove-Josserand Eric Oksenhendler Marie Ouachée-Chardin Caroline Oudot Anne Pagnier Jean-Louis Pasquali Marlène Pasquet Yves Perel Capucine Picard Christophe Piguet Dominique Plantaz Johan Provot Pierre Quartier Frédéric Rieux-Laucat Pascal Roblot Pierre-Marie Roger Pierre-Simon Rohrlich Hervé Rubie Valéry Salle Françoise Sarrot-Reynauld Amélie Servettaz Jean-Louis Stephan Nicolas Schleinitz Felipe Suarez Laure Swiader Sophie Taque Caroline Thomas Olivier Tournilhac Caroline Thumerelle François Tron Jean-Pierre Vannier Jean-François Viallard

J Clin Immunol 2019 10 10;39(7):702-712. Epub 2019 Aug 10.

Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.

Purpose: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles.

Methods: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included.

Results: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04).

Conclusion: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.
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http://dx.doi.org/10.1007/s10875-019-00658-9DOI Listing
October 2019

[Immunotherapy of cancers by inhibiting control of the immune response honored by a Nobel Prize].

Authors:
Yvon Lebranchu

Rev Prat 2019 Mar;69(3):243-246

Professeur émérite de l'université de Tours, Tours, France Académie nationale de médecine, Paris, France.

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March 2019

Prognostic Value of the Persistence of C1q-Binding Anti-HLA Antibodies in Acute Antibody-Mediated Rejection in Kidney Transplantation.

Transplantation 2018 04;102(4):688-698

Department of Nephrology and Kidney Transplantation, University Hospital of Tours, Tours, France.

Background: The differential pathogenicity of anti-HLA donor-specific antibodies (DSAs) is not fully understood. The presence of complement-binding DSAs helps in better defining the prognosis of acute antibody-mediated rejection (ABMR). The evolution of these antibodies after the treatment of ABMR is unknown.

Methods: We included patients from the French multicenter RITUX ERAH study diagnosed with acute ABMR within the first year of renal transplantation, with circulating anti-HLA DSAs and treated randomly by rituximab or placebo (and intravenous immunoglobulins, plasma exchange). We centrally analyzed serum samples at the time of ABMR, 3 and 6 months after ABMR, with anti-HLA DSAs specificities and C1q-binding capacity assessment.

Results: Twenty-five patients were included: 68% had C1q-binding DSAs at the time of ABMR. The presence of C1q-binding DSAs was associated with a poorer evolution of chronic glomerulopathy at 6 months (P = 0.036). The persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR was associated with more severe chronic glomerulopathy (P = 0.006), greater C4d score deposition score at 6 months after ABMR (P = 0.008), and graft loss 5 years after ABMR (P = 0.029). C1q-binding capacity was associated with the DSA MFI but 5 C1q-binding DSAs in 4 patients had low MFI values without a prozone effect.

Conclusion: The presence and persistence of anti-HLA C1q-binding DSAs after ABMR is a detrimental marker, leading to transplant glomerulopathy and graft loss. Assessment of the complement-binding capacities of DSAs could help decide treatment intensification.
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http://dx.doi.org/10.1097/TP.0000000000002002DOI Listing
April 2018

Complement-Activating Anti-HLA Antibodies in Kidney Transplantation: Allograft Gene Expression Profiling and Response to Treatment.

J Am Soc Nephrol 2018 02 17;29(2):620-635. Epub 2017 Oct 17.

Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France.

Complement-activating anti-HLA donor-specific antibodies (DSAs) are associated with impaired kidney transplant outcome; however, whether these antibodies induce a specific rejection phenotype and influence response to therapy remains undetermined. We prospectively screened 931 kidney recipients for complement-activating DSAs and used histopathology, immunostaining, and allograft gene expression to assess rejection phenotypes. Effector cells were evaluated using human cell cultures. Additionally, we assessed the effect of complement inhibition on kidney allograft rejection phenotype and the clinical response to complement inhibition in 116 independent kidney recipients with DSAs at transplant receiving rejection prophylaxis with eculizumab or standard of care (plasma exchange and intravenous Ig) at ten international centers. The histomolecular rejection phenotype associated with complement-activating DSA was characterized by complement deposition and accumulation of natural killer cells and monocytes/macrophages in capillaries and increased expression of five biologically relevant genes (, , , , and ) indicative of endothelial activation, IFN response, CD16-mediated natural killer cell activation, and monocyte/macrophage activation. Compared with standard of care, eculizumab specifically abrogated this histomolecular rejection phenotype and associated with a decreased 3-month rejection incidence rate in patients with complement-activating DSAs (56%; 95% confidence interval [95% CI], 38% to 74% versus 19%; 95% CI, 8% to 35%; =0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%; =0.65). In conclusion, circulating complement-activating anti-HLA DSAs are associated with a specific histomolecular kidney allograft rejection phenotype that can be abrogated by complement inhibition.
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http://dx.doi.org/10.1681/ASN.2017050589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791056PMC
February 2018

Polymorphism in programmed cell death 1 gene is strongly associated with lung and kidney allograft survival in recipients from CMV-positive donors.

J Heart Lung Transplant 2017 Mar 26;36(3):315-324. Epub 2016 Aug 26.

EA4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais, Tours.

Background: Cytomegalovirus (CMV) has a role in chronic rejection and graft loss in kidney transplant (KTx) and lung transplant (LTx) recipients. In addition, donor CMV seropositivity is an independent risk factor for renal graft loss. The anti-CMV response might modulate this risk. Expression of programmed cell death 1 (PD-1), a receptor involved in viral-specific T-cell exhaustion, is influenced by a single nucleotide polymorphism called PD-1.3 (wild-type allele G, variant allele A).

Methods: We performed a retrospective study to assess the impact of PD-1.3 on graft outcome in donor CMV seropositive (D+) and donor CMV seronegative (D-) KTx and LTx. We also performed a case-control study to evaluate the anti-CMVpp65 response according to genotype.

Results: PD-1.3 was determined in 1,119 KTx and 181 LTx. In 481 D+ KTx, A allele carriers (24%) experienced significantly less graft failure compared with GG carriers (p = 0.001). Multivariate analysis showed that this association was independent of donor and recipient age, acute rejection episodes, and number of human leukocyte antigen mismatches (hazard ratio, 0.381; 95% confidence interval, 0.209-0.696; p = 0.002). Analysis in 85 D+ LTx showed similar results: A allele carriers had better survival (hazard ratio, 0.302; 95% confidence interval, 0.128-0.716; p = 0.006) and greater 6-month forced expiratory volume (71% ± 17% vs 54% ± 16%, p = 0.001). In D- recipients, PD-1.3 did not affect KTx or LTx outcome. Finally, AA recipients had a stronger anti-CMVpp65 T-cell response than matched GG recipients (p = 0.003).

Conclusions: The A variant allele in PD-1.3 single nucleotide polymorphism improved graft survival in kidney and lung transplant recipients receiving grafts from CMV-positive donors.
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http://dx.doi.org/10.1016/j.healun.2016.08.014DOI Listing
March 2017

Unexpected impairment of TNF-α-induced maturation of human dendritic cells in vitro by IL-4.

J Transl Med 2016 Apr 14;14:93. Epub 2016 Apr 14.

UFR de Médecine, UPRES EA 4245 "Cellules Dendritiques, Immunomodulation et Greffes", Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032, Tours, France.

Background: An efficient strategy for programming dendritic cells (DCs) for cancer immunotherapy is the optimization of their maturation so that they can efficiently stimulate cancer-specific T cell responses. Interleukin (IL)-4 has appeared as an essential cytokine, widely used in vitro with granulocyte macrophage-colony stimulating factor (GM-CSF) to differentiate monocytes into immature DCs (iDC) and to prevent macrophage formation. Conflicting data have been published regarding the effect of IL-4 on functional DC maturation. To further understand IL-4's effects on DC maturation and function in vitro, we choose the most commonly used maturation factor tumor necrosis factor (TNF)-α.

Methods: Human monocyte-derived iDC were treated for 48 h with GM-CSF and TNF-α in the presence (IL-4(+)-DC) or absence (IL-4(-)-DC) of IL-4 and functions of both DC populations were compared.

Results: On mixed lymphocyte reaction assay, IL-4(+)-DC were less potent than IL-4(-)-DC at inducing the proliferation of allogeneic CD4(+) T cells and the proportion of activated T cells expressing CD69 and/or CD25 was smaller. Interleukin-4 reduced the cell-surface expression of TNF-α-induced DC maturation markers CD83, CD86, HLA-DR and CD25 and generated a heterogeneous population of DCs. IL-4(+)-DC secreted less IL-12 and more IL-10 than IL-4(-)-DC following activation by soluble CD40L, and IL-4(+)-DC-activated T cells secreted lesser amounts of T helper (Th) 1 cytokines (IL-2 and interferon-γ). Importantly, IL-4 impaired the in vitro migratory capacity of DCs in response to CCL21 and CCL19 chemokines. This effect was related to reduced expression of CCR7 at both mRNA and protein levels.

Conclusion: Interleukin-4 used with GM-CSF and TNF-α during the maturation of DCs in vitro impaired DC functions and disturbed the maturation effect of TNF-α. Finally, our study reinforces the view that the quality of the DC maturation stimulus, which regulates DC migration and cytokine production, may be a decisive feature of the immunogenicity of DCs.
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http://dx.doi.org/10.1186/s12967-016-0848-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832484PMC
April 2016

[Not Available].

Authors:
Yvon Lebranchu

Bull Acad Natl Med 2016 Feb;200(2):285-290

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February 2016

One-year Results of the Effects of Rituximab on Acute Antibody-Mediated Rejection in Renal Transplantation: RITUX ERAH, a Multicenter Double-blind Randomized Placebo-controlled Trial.

Transplantation 2016 Feb;100(2):391-9

1 Service de Néphrologie-Immunologie Clinique, CHU Bretonneau, Tours, France. 2 Université François-Rabelais, Tours, France. 3 Institut de Transplantation, Urologie-Néphrologie (ITUN), CHU, Nantes, France. 4 Université François-Rabelais, Tours, France. 5 Service de Néphrologie, CHU Edouard Herriot, Lyon, France. 6 Service de Néphrologie, CHU Maison Blanche, Reims, France. 7 Service d'Urologie, CHU Pitié Salpêtrière, Paris, France. 8 Service de Néphrologie, CHU Jean Minjoz, Besançon, France. 9 Service de Néphrologie, CHU, Caen, France. 10 Service de Néphrologie, CHU Civil, Strasbourg, France. 11 Service de Néphrologie, CHU, Rouen, France. 12 Service de Néphrologie, CHU, Lille, France. 13 Service de Néphrologie, CHU Henri Mondor, Paris, France. 14 Service de Néphrologie, CHU Necker, Paris, France. 15 Service de Néphrologie-Transplantation-Dialyse, CHU Pellegrin, Bordeaux, France. 16 Service de Néphrologie, CHU, Montpellier, France. 17 Service de Néphrologie, CHU, Dijon, France. 18 Service de Néphrologie, CHU, Lyon, France. 19 Service de Néphrologie, CHU, Marseille, France. 20 Service de Néphrologie, CHU, Limoges, France. 21 Service de Néphrologie-Dialyse-Transplantation, CHU, Angers, France. 22 Service de Néphrologie, CHU, Amiens, France. 23 Service de Néphrologie, CHU, Grenoble, France. 24 Service de Pharmacologie Clinique, CHU Bretonneau, Tours, France. 25 INSERM, CIC 1415, CHU Bretonneau, Tours, France.

Background: Treatment of acute antibody-mediated rejection (AMR) is based on a combination of plasma exchange (PE), IVIg, corticosteroids (CS), and rituximab, but the place of rituximab is not clearly specified in the absence of randomized trials.

Methods: In this phase III, multicenter, double-blind, placebo-controlled trial, we randomly assigned patients with biopsy-proven AMR to receive rituximab (375 mg/m) or placebo at day 5. All patients received PE, IVIg, and CS. The primary endpoint was a composite of graft loss or no improvement in renal function at day 12.

Results: Among the 38 patients included, at 1 year, no deaths occurred, but 1 graft loss occurred in each group. The primary endpoint frequency was 52.6% (10/19) and 57.9% (11/19) in the rituximab and placebo groups, respectively (P = 0.744). Renal function improved in both groups, as soon as day 12 with no difference in serum creatinine level and proteinuria at 1, 3, 6, and 12 months. Supplementary administration of rituximab and total number of IVIg and PE treatments did not differ between the 2 groups. Both groups showed improved histological features of AMR and Banff scores at 1 and 6 months, with no significant difference between groups but with a trend in favor of the rituximab group. Both groups showed decreased mean fluorescence intensity of donor-specific antibodies as soon as day 12, with no significant difference between them but with a trend in favor of the rituximab group at 12 months.

Conclusions: After 1 year of follow-up, we observed no additional effect of rituximab in patients receiving PE, IVIg, and CS for AMR. Nevertheless, our study was underpowered and important differences between groups may have been missed. Complementary trials with long-term follow-up are needed.
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http://dx.doi.org/10.1097/TP.0000000000000958DOI Listing
February 2016

CD25 blockade in kidney transplant patients randomized to standard-dose or high-dose basiliximab with cyclosporine, or high-dose basiliximab in a calcineurin inhibitor-free regimen.

Transpl Int 2016 Feb 8;29(2):184-95. Epub 2015 Oct 8.

Department of Nephrology and Clinical Immunology, Bretonneau Hospital, CHRU de Tours, EA4245, Université François-Rabelais de Tours, Tours, France.

An increased basiliximab dose may saturate T-cell CD25 receptors in kidney transplant patients receiving calcineurin inhibitor (CNI)-free immunosuppression. In a 12-week study, 16 de novo kidney transplant patients were randomized to (i) 40 mg basiliximab with cyclosporine [n = 3] (controls), (ii) 80 mg basiliximab with cyclosporine [n = 6], or (iii) 80 mg basiliximab with everolimus (CNI-free) [n = 7], all with mycophenolic acid and steroids. Recruitment was stopped prematurely due to increased biopsy-proven acute rejection (BPAR) in the basiliximab 80 mg CNI-free group. BPAR occurred in 1/3, 1/6, and 4/7 patients in the three treatment groups, respectively. The primary endpoint, area under the effect curve of CD25 saturation to week 12, was 8.4(1.6) % × weeks in the control group, 11.1(1.1) % × weeks with basiliximab 80 mg + cyclosporine, and 9.7(0.7) % × weeks in the basiliximab 80 mg CNI-free group (P = 0.020 for basiliximab 80 mg + cyclosporine versus controls; P = 0.119 for basiliximab 80 mg CNI-free versus controls). Although small patient numbers prohibit robust conclusions, these results suggest that doubling the cumulative basiliximab dose to 80 mg does not provide adequate immunosuppression during the first 3 months after kidney transplantation in the absence of CNI therapy (ClinicalTrials.gov number: NCT01596062).
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http://dx.doi.org/10.1111/tri.12688DOI Listing
February 2016

Eight-year results of the Spiesser study, a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation.

Transpl Int 2016 Jan;29(1):41-50

Service de Néphrologie et Immunologie clinique, CHRU de Tours, Tours, France.

We present the results at 8 years of the Spiesser study, a randomized trial comparing de novo sirolimus and cyclosporine in kidney transplant recipients at low immunologic risk. We assessed estimated glomerular filtration (eGFR), graft, patient, and death-censored graft survival (log-rank compared), de novo DSA appearance, risk of malignancy, post-transplant diabetes mellitus (PTDM), and anemia. Intent-to-treat and on-treatment analyses were performed. Graft survival was similar in both groups (sirolimus: 73.3%, cyclosporine: 77.7, P = 0.574). No difference was observed between treatment groups concerning patient survival (P = 0.508) and death-censored graft survival (P = 0.858). In conditional intent-to-treat analysis, mean eGFR was greater in sirolimus than in cyclosporine group (62.5 ± 27.3 ml/min vs. 47.8 ± 17.1 ml/min, P = 0.004), in particular because graft function was excellent in patients maintained under sirolimus (eGFR = 74.0 ml/min). Importantly, no detrimental impact was observed in patients in whom sirolimus has been withdrawn (eGFR = 49.5 ml/min). Overall, 17 patients showed de novo DSAs, with no difference between the two groups (P = 0.520). Malignancy did not differ by treatment. An initial maintenance regimen based on sirolimus provides a long-term improvement in renal function for kidney transplant patients, especially for those maintained on sirolimus.
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http://dx.doi.org/10.1111/tri.12656DOI Listing
January 2016

New directions for rabbit antithymocyte globulin (Thymoglobulin(®)) in solid organ transplants, stem cell transplants and autoimmunity.

Drugs 2014 Sep;74(14):1605-34

Department of Hematology and Cellular Therapy, CHU Hôpital Saint Antoine, 184, rue du Faubourg Saint Antoine, 75571, Paris Cedex 12, France,

In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin(®) was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn's disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.
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http://dx.doi.org/10.1007/s40265-014-0277-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180909PMC
September 2014

IL-2 phosphorylates STAT5 to drive IFN-γ production and activation of human dendritic cells.

J Immunol 2014 Jun 14;192(12):5660-70. Epub 2014 May 14.

L'Équipe d'Accueil 4245, Université François Rabelais, 37032 Tours, France; Service de Néphrologie et d'Immunologie Clinique, Centre Hospitalier Régional Universitaire de Tours, 37044 Tours, France.

Human dendritic cells (hDCs) produce IL-2 and express IL-2R α-chain (CD25), but the role of IL-2 in DC functions is not well defined. A recent study suggested that the main function of CD25 on hDCs was to transpresent IL-2 to activate T lymphocytes. Our results demonstrate the expression of the three chains of the IL-2R on hDCs and that IL-2 induces STAT5 phosphorylation. Interestingly, use of inhibitors of p-STAT5 revealed that IL-2 increases LPS-induced IFN-γ through STAT5 phosphorylation. Finally, we report that IL-2 increases the ability of hDCs to activate helpless CD8(+) T cells, most likely because of IL-2-triggered IFN-γ synthesis, as we previously described. For the first time, to our knowledge, we disclose that IL-2 induces monocyte-derived hDC's functional maturation and activation through IL-2R binding. Interestingly, our study suggests a direct effect of anti-CD25 mAbs on hDCs that may contribute to their clinical efficacy.
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http://dx.doi.org/10.4049/jimmunol.1300422DOI Listing
June 2014

Conversion to mTOR-inhibitor-based immunosuppression: which patients and when?

Transplant Res 2013 Nov 20;2(Suppl 1):S3. Epub 2013 Nov 20.

Mammalian target of rapamycin (mTOR) inhibitors are currently considered an alternative immunosuppressive treatment that can prevent the nephrotoxicity, viral infections and malignancies that are associated with calcineurin inhibitor-based immunosuppressive regimens. However, the side effects of mTOR-inhibitor-based regimens lead to frequent treatment discontinuations, and not all patients seem to have the same benefits from conversion to mTOR inhibitors. This review focuses on long-term results of trials that have assessed early and late conversion to sirolimus or everolimus. The renal benefit of late conversion (≥1 year post transplantation) is limited, except in patients with good renal function and without proteinuria. Early conversion to mTOR inhibitors in the first 6 months, in combination with mycophenolate mofetil, could be an appropriate strategy for maintenance therapy in renal transplant recipients with a low immunological risk after careful screening at the time of conversion. Good renal function (glomerular filtration rate >40 ml/ minute), weak proteinuria (<1 g/day), an absence of previous acute rejection and subclinical rejection, and appearance of donor-specific anti-human leukocyte antigen antibodies appear to be the most important criteria in identifying patients for whom conversion to an mTOR inhibitor may improve renal function at 5 years.
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http://dx.doi.org/10.1186/2047-1440-2-S1-S3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834549PMC
November 2013

Influence of FcγRIIIA genetic polymorphism on T-lymphocyte depletion induced by rabbit antithymocyte globulins in kidney transplant patients.

Pharmacogenet Genomics 2014 Jan;24(1):26-34

aFrançois Rabelais University of Tours bCNRS, UMR 7292 'GICC' University of Tours cLaboratory of Pharmacology-Toxicology, University Hospital of Tours dLaboratory of Immunology eDepartment of Nephrology and Clinical Immunology, Tours, France.

Introduction: Polyclonal antithymocyte globulins (ATG) have been used in transplantation for several decades, but the sources of the interindividual variability of their effect are poorly understood. An influence of the FCGR3A-158V/F genetic polymorphism on the horse ATG concentration-effect relationship was reported in kidney transplant patients. The objective of the present study was to confirm the influence of the FCGR3A polymorphism on the extent of lymphocyte depletion in kidney transplant patients treated with rabbit antithymocyte globulin (r-ATG).

Materials And Methods: Of the 194 transplant patients treated with r-ATG between 1998 and 2002 in our institution, 69 patients were eligible and included in this retrospective study. Biomarkers of response were CD3 and CD4 counts. Dose-effect data were analyzed using a population approach, and a two-compartment turnover model with stimulation of lymphocyte 'output'. Since r-ATG concentrations were not available, a K-PD model was used. The influence of FCGR3A genotype on estimated parameters was investigated.

Results: The r-ATG infusion rate leading to a 50% stimulation of CD3+ output (EDK(50)), which is inversely related to patient sensitivity to r-ATG treatment, decreased with the number of V alleles (P=0.0016).

Conclusion: The genetic polymorphism of FCGR3A influences r-ATG effect on CD3 count in kidney transplant patients, those with the V allele being more sensitive to antilymphocyte serum. These results also suggest that r-ATG act, at least in part, by antibody-dependent cellular cytotoxicity.
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http://dx.doi.org/10.1097/FPC.0000000000000017DOI Listing
January 2014

Progression of pulse pressure in kidney recipients durably exposed to CsA is a risk factor for epithelial phenotypic changes: an ancillary study of the CONCEPT trial.

Transpl Int 2014 Apr 28;27(4):344-52. Epub 2014 Jan 28.

Département de Santé Publique, APHP, Hôpital Tenon, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S1155, Paris, France.

In this ancillary study of the CONCEPT trial, we studied the role of CsA withdrawal at 3 months (3M) post-transplant on the intensity of epithelial phenotypic changes (EPC, an early marker for kidney fibrogenesis) on the 12 M surveillance biopsy. Although conversion from CsA to sirolimus (SRL) at 3M was reported to have improved mean graft function at 12 M, it did not reduce the score of EPC (1.73 ± 1.15 in the SRL group vs. 1.87 ± 1 in the CsA group, P = 0.61). Acute rejection, which had occurred twice more frequently in SRL-converted patients included here, was associated with 12 M EPC. Interestingly, we observed that the patients durably exposed to CsA and who developed 12 M EPC had a significant progression of blood pulse pressure (pp) from 1 to 6M post-transplantation (Δpp = +12.3 mmHg, P = 0.0035). Pulse pressure at 4, 6, and 9 M and pp progression from 1 to 6M were significantly associated with the development of EPC at 12 M in renal grafts. Logistic regression analysis revealed that a high 6M pp (≥ 60 mmHg) was an independent risk factor for 12 M EPC with an odds ratio of 2.25 per additional 10 mmHg pp (95%CI: 1.14-4.4, P = 0.02) after adjustment with recipient's and donor's age, acute rejection incidence and immunosuppressive regimen. A post hoc analysis of the data collected in the whole population CONCEPT study revealed that pp was significantly higher at 6 months in patients maintained on CsA and that at this time point pp correlated negatively with GFR at 1 year.
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http://dx.doi.org/10.1111/tri.12253DOI Listing
April 2014

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

Transpl Int 2014 Mar 27;27(3):271-9. Epub 2013 Dec 27.

Department of Nephrology and Clinical Immunology, CHRU Tours, Tours, France.

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.
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http://dx.doi.org/10.1111/tri.12249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282399PMC
March 2014

Mycophenolic acid-treated dendritic cells generate regulatory CD4+ T cells that suppress CD8+ T cells' allocytotoxicity.

Int Immunol 2014 Mar 12;26(3):173-81. Epub 2013 Nov 12.

UPRES EA 4245 « Cellules Dendritiques, Immunomodulation et Greffes », UFR de Médecine, Université François-Rabelais, 10 Boulevard Tonnellé, 37000 Tours, France.

Regulatory T cells (Treg) play a crucial role in controlling immunity and transplant rejection. Two main groups of Treg have been described: antigen-induced Treg (iTreg) and natural Treg (nTreg). The ways to induce and the mechanisms of action of Treg subsets remained ill defined, particularly for their effects on CD8(+) T cells. CD8(+) T cells are major agents in the rejection of allografts; the aim of this study is to investigate the effects exerted on CD8(+) T cells by human CD4(+) iTreg induced by mycophenolic acid-treated dendritic cells. iTreg suppress the proliferation of CD8(+) T cells by allogeneic cell-cell interaction with mature dendritic cells and irrespectively of the TCR specificity of the CD8(+) T cells and cell-cell contact of iTreg with CD8(+) T cells. In our model, this suppression is independent of the action of IL-10 and TGF-β1. iTreg were able to modify phenotype and inhibited IFN-γ and TNF-α secretion by CD8(+) T cells. Most interestingly, iTreg inhibit the synthesis of perforin and of granzymes A and B by CD8(+) T cells and impaired their cytotoxicity against allogeneic targets. In summary, our study showed the involvement of iTreg in the down-regulation of cytotoxic responses mediated by CD8(+) T cells in an allospecific context. Following studies that have shown the existence of a regulation control exerted by iTreg on CD4(+) T cells and dendritic cells, this work ultimately shows that this regulation can reach CD8(+) T-cell functions.
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http://dx.doi.org/10.1093/intimm/dxt054DOI Listing
March 2014

Pretransplant identification of acute rejection risk following kidney transplantation.

Transpl Int 2014 Feb 25;27(2):129-38. Epub 2013 Oct 25.

Department of Nephrology and Clinical Immunology, EA 4245, CHRU Tours, Tours, France.

Lack of an accepted definition for 'high immunological risk' hampers individualization of immunosuppressive therapy after kidney transplantation. For recipient-related risk factors for acute rejection, the most compelling evidence points to younger age and African American ethnicity. Recipient gender, body mass, previous transplantation, and concomitant infection or disease do not appear to be influential. Deceased donation now has only a minor effect on rejection risk, but older donor age remains a significant predictor. Conventional immunological markers (human leukocyte antigen [HLA] mismatching, pretransplant anti-HLA alloantibodies, and panel reactive antibodies) are being reassessed in light of growing understanding about the role of donor-specific antibodies (DSA). At the time of transplant, delayed graft function is one of the most clear-cut risk factors for acute rejection. Extended cold ischemia time (≥ 24 h) may also play a contributory role. While it is not yet possible to establish conclusively the relative contribution of different risk factors for acute rejection after kidney transplantation, the available data point to variables that should be taken into account at the time of transplant. Together, these offer a realistic basis for planning an appropriate immunosuppression regimen in individual patients.
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http://dx.doi.org/10.1111/tri.12205DOI Listing
February 2014

Very low residual concentrations of rituximab long after infusion still induce positive B-cell complement-dependent cytotoxicity-crossmatch.

Hum Immunol 2013 Dec 29;74(12):1616-8. Epub 2013 Aug 29.

CHRU de Tours, Department of Nephrology and Transplantation, Tours, France; Université François-Rabelais, EA 4245 Tours, France.

Rituximab may induce positive B-cell complement-dependent cytotoxicity crossmatch (CDC-XM) in the absence of donor-specific antibodies, as we report in these two cases. We retrospectively assessed the in vitro concentration-effect relationship of rituximab in sera. B-cell CDC-XM results were positive only in the presence of rituximab, even with low concentrations (inferior to 1 μg/mL). Moreover, rituximab neutralization with increasing concentration of an anti-rituximab-idiotype monoclonal antibody progressively reduced B-cell lysis. In conclusion, measurement of rituximab content may be useful to identify sera at risk of misinterpretation in immunized patients.
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http://dx.doi.org/10.1016/j.humimm.2013.08.278DOI Listing
December 2013

The Orai-1 and STIM-1 complex controls human dendritic cell maturation.

PLoS One 2013 20;8(5):e61595. Epub 2013 May 20.

EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François Rabelais, IFR-136 Agents Transmissibles et Infectiologie, UFR de Médecine, Tours, France.

Ca(2+) signaling plays an important role in the function of dendritic cells (DC), the professional antigen presenting cells. Here, we described the role of Calcium released activated (CRAC) channels in the maturation and cytokine secretion of human DC. Recent works identified STIM1 and Orai1 in human T lymphocytes as essential for CRAC channel activation. We investigated Ca(2+) signaling in human DC maturation by imaging intracellular calcium signaling and pharmalogical inhibitors. The DC response to inflammatory mediators or PAMPs (Pathogen-associated molecular patterns) is due to a depletion of intracellular Ca(2+) stores that results in a store-operated Ca(2+) entry (SOCE). This Ca(2+) influx was inhibited by 2-APB and exhibited a Ca(2+)permeability similar to the CRAC (Calcium-Released Activated Calcium), found in T lymphocytes. Depending on the PAMPs used, SOCE profiles and amplitudes appeared different, suggesting the involvement of different CRAC channels. Using siRNAi, we identified the STIM1 and Orai1 protein complex as one of the main pathways for Ca(2+) entry for LPS- and TNF-α-induced maturation in DC. Cytokine secretions also seemed to be SOCE-dependent with profile differences depending on the maturating agents since IL-12 and IL10 secretions appeared highly sensitive to 2-APB whereas IFN-γ was less affected. Altogether, these results clearly demonstrate that human DC maturation and cytokine secretions depend on SOCE signaling involving STIM1 and Orai1 proteins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061595PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659124PMC
December 2013

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

Transpl Immunol 2013 Mar 16;28(2-3):120-6. Epub 2013 Mar 16.

Université François Rabelais, Tours, France; CHRU Tours, Département de Néphrologie et Immunologie Clinique, Tours, France.

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 6mg/kg, administered either as 1.5mg/kg/day on days 0-3 (Group 1, n=8) or 3mg/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 rATG 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±1.1μg/mL versus 10.2±2.9μg/mL in Group 2, p=0.027) and total rATG dose-normalized AUC (374±83dayg/mL versus 508±149dayg/mL in Group 2, p=0.046). Time to sub-therapeutic levels (<1μg/mL) of active rATG was significantly shorter in Group 1 (18.75±6.9days versus 20±7.5days 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-cell count was unaffected, whereas CD3(-)CD56(+) NK-cell depletion was observed in both groups. rATG induced a significant decrease in the proportion of naïve 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.
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http://dx.doi.org/10.1016/j.trim.2013.03.001DOI Listing
March 2013

Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score.

J Clin Oncol 2013 Apr 19;31(10):1302-9. Epub 2013 Feb 19.

Nephrology-Transplantation Department, Strasbourg University Hospital, Strasbourg, France.

Purpose: Post-transplantation lymphoproliferative disorder (PTLD) is associated with significant mortality in kidney transplant recipients. We conducted a prospective survey of the occurrence of PTLD in a French nationwide population of adult kidney recipients over 10 years.

Patients And Methods: A French registry was established to cover a nationwide population of transplant recipients and prospectively enroll all adult kidney recipients who developed PTLD between January 1, 1998, and December 31, 2007. Five hundred patient cases of PTLD were referred to the French registry. The prognostic factors for PTLD were investigated using Kaplan-Meier and Cox analyses.

Results: Patients with PTLD had a 5-year survival rate of 53% and 10-year survival rate of 45%. Multivariable analyses revealed that age > 55 years, serum creatinine level > 133 μmol/L, elevated lactate dehydrogenase levels, disseminated lymphoma, brain localization, invasion of serous membranes, monomorphic PTLD, and T-cell PTLD were independent prognostic indicators of poor survival. Considering five variables at diagnosis (age, serum creatinine, lactate dehydrogenase, PTLD localization, and histology), we constructed a prognostic score that classified patients with PTLD as being at low, moderate, high, or very high risk for death. The 10-year survival rate was 85% for low-, 80% for moderate-, 56% for high-, and 0% for very high-risk recipients.

Conclusion: This nationwide study highlights the prognostic factors for PTLD and enables the development of a new prognostic score. After validation in an independent cohort, the use of this score should allow treatment strategies to be better tailored to individual patients in the future.
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http://dx.doi.org/10.1200/JCO.2012.43.2344DOI Listing
April 2013

Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.

Clin J Am Soc Nephrol 2013 Apr 10;8(4):554-62. Epub 2013 Jan 10.

Service d'Immunologie Biologique, Hôpital Europeén Georges Pompidou, 20-40 rue Leblanc, Paris cedex 15, France.

Background And Objectives: Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated kidney disease that was first recognized in children but also affects adults. This study assessed the disease presentation and outcome in a nationwide cohort of patients with aHUS according to the age at onset and the underlying complement abnormalities.

Design, Setting, Participants, & Measurements: A total of 214 patients with aHUS were enrolled between 2000 and 2008 and screened for mutations in the six susceptibility factors for aHUS and for anti-factor H antibodies.

Results: Onset of aHUS occurred as frequently during adulthood (58.4%) as during childhood (41.6%). The percentages of patients who developed the disease were 23%, 40%, 70%, and 98% by age 2, 18, 40, and 60 years, respectively. Mortality was higher in children than in adults (6.7% versus 0.8% at 1 year) (P=0.02), but progression to ESRD after the first aHUS episode was more frequent in adults (46% versus 16%; P<0.001). Sixty-one percent of patients had mutations in their complement genes. The renal outcome was not significantly different in adults regardless of genetic background. Only membrane cofactor protein (MCP) and undetermined aHUS were less severe in children than adults. The frequency of relapse after 1 year was 92% in children with MCP-associated HUS and approximately 30% in all other subgroups.

Conclusion: Mortality rate was higher in children than adults with aHUS, but renal prognosis was worse in adults than children. In children, the prognosis strongly depends on the genetic background.
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http://dx.doi.org/10.2215/CJN.04760512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613948PMC
April 2013

Prognostic significance of graft Foxp3 expression in renal transplant recipients: a critical review and attempt to reconcile discrepancies.

Nephrol Dial Transplant 2013 May 21;28(5):1100-11. Epub 2012 Dec 21.

Department of Renal Transplantation, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

A large body of evidence has been accumulated from experimental models in the past decade to support the critical role of Foxp3-expressing regulatory T cells (Tregs) in the suppression of alloimmune responses. This has prompted transplant clinicians to investigate whether Foxp3 analysis might be used as an immunodiagnostic tool for better assessment of the significance of graft infiltrate and to predict its impact on graft outcome. However, conflicting results have emerged from these studies and may have generated more confusion than clarification. Foxp3 expression has been antagonistically correlated with either good or poor prognosis. We discuss here how methodological issues and specific clinical settings may have accounted for the discrepancies between the results of these studies. Depending on many factors, including the techniques used, the method of sampling normalization, the extent of intra-graft inflammation, the immunosuppressive regimen and the depletion or repletion of T lymphocyte compartment, the significance of Foxp3 expression may vary. We propose here the conditions to be fulfilled in order to use Foxp3 analysis as a relevant biomarker for graft outcome assessment. Far from challenging the key role of Tregs in dampening alloimmune responses, this review highlights the need for technical harmonization and standards.
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http://dx.doi.org/10.1093/ndt/gfs570DOI Listing
May 2013

The role of Thymoglobulin induction in kidney transplantation: an update.

Clin Transplant 2012 Sep-Oct;26(5):E450-64

Department of Nephrology and Transplantation, Hôpital Lapeyronie, University of Montpellier Medical School, Montpellier.

The rabbit antithymocyte globulin Thymoglobulin first became available over 25 yr ago and is the most widely used lymphocyte-depleting preparation in solid organ transplantation. Thymoglobulin targets a wide range of T-cell surface antigens as well as natural killer-cell antigens, B-cell antigens, plasma cell antigens, adhesion molecules and chemokine receptors, resulting in profound, long-lasting T-cell depletion. Randomized studies have established the anti-rejection efficacy of Thymoglobulin in kidney transplantation. Experimental and clinical data suggest that Thymoglobulin administration may ameliorate ischemia reperfusion injury, thus reducing the incidence of delayed graft function (DGF). Studies have demonstrated the benefit of using Thymoglobulin to facilitate immunosuppression minimization, both for corticosteroid and calcineurin inhibitor (CNI) withdrawal or avoidance, with potential improvement in cardiovascular and renal outcomes. The optimal cumulative dose for Thymoglobulin induction is 6-7.5 mg/kg, with vigilant short- and long-term monitoring of hematological status. Induction with Thymoglobulin is now indicated in immunologically high-risk patients, in those at increased risk of DGF and to maintain efficacy in low-risk transplant recipients receiving steroid or CNI minimization or avoidance regimens. We suggest that in future trials Thymoglobulin be tested with costimulation signal blockers and other immunosuppressants with the objective of establishing operational tolerance.
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http://dx.doi.org/10.1111/ctr.12021DOI Listing
March 2013

Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey.

Medicine (Baltimore) 2012 Jul;91(4):e1-e19

From the Hematology Department (MOC, FS, OH), Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris; University Paris Descartes (MOC, IM, AN, AP, LY, SB, AD, CB, FS, OH, OL, JLC, AF, CP), Necker Medical School, Paris; Laboratory of Human Genetics of Infectious Diseases (IM, AN, AP, LY, JLC, CP), Necker Branch, INSERM U980, Paris; Clinical Immunology Department (CF, EO), Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris; EA 3963 (CF, DB), Saint-Louis Hospital, University Paris 7, Paris; Pediatric Pulmonary Department (C. Thumerelle), Jeanne de Flandres Hospital, Lille; Pediatric Hemato-Oncology Department (C. Thomas), Nantes Hospital, Nantes; Immunology Unit (C. Hoarau, YL), Tours Hospital, Tours; Pediatric Hemato-Oncology Department (JLS), Saint-Etienne Hospital, Saint-Etienne; Department of Infectious Diseases (CC), Saint-Etienne Hospital, Saint-Etienne; Pediatric Hemato-Oncology Department (NA, M. Micheau), Pellegrin Hospital, Bordeaux; Immunology Unit (FT), Rouen Hospital, Rouen; Pediatric Hemato-Oncology Department (AB),Robert Debré Hospital, Assistance Publique Hôpitaux de Paris, Paris; Pediatric Hemato-Oncology Department (VB), Timone Hospital, Marseille; PediatricDepartment (GP), Béziers Hospital, Béziers; Pediatric Department(CM), Aix-en-Provence Hospital, Aix-en-Provence; Pulmonary Department (SD), Rouen Hospital, Rouen; Pediatric Pulmonary Department (GB), Châlons-en-Champagne Hospital, Châlons-en-Champagne; Pediatric Hemato-Oncology Department (M. Munzer), Reims Hospital, Reims; Pediatric Hemato-Oncology Department (FF), Nancy Hospital, Nancy; Internal Medicine, Infectious Diseases, Immunology Clinic (RJ), Hôpital Robert Debré, Reims Hospital, Reims; Pediatric Immuno-Hematology Unit (BBM, NM, SB, MD, JLC, AF, CP), Necker Children's Hospital, Assistance Publique Hôpitaux de Paris, Paris; Centre de Référence des Déficits Immunitaires Héréditaires (CEREDIH) (MOC, NM, AD, FS, OH, OL, AF, CP), Necker-Enfants Malades Hospital, Paris; Pediatric Pulmonary Department (MLB), Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris; Pediatric Hemato-Oncology Department (V. Gandemer), Rennes Hospital, Rennes; Study Center for Primary Immunodeficiencies (NL, V. Grandin, SN, CJ, C. Harre, MF, AD, CP), Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris; Immunology Laboratory (MAA), Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris; INSERM U768 (AD, AF), Necker-Enfants Malades Hospital, Paris; Pediatric Dermatology Department (CB), Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris; Department of Infectious Diseases and Tropical Medicine (OL), Assistance Publique Hôpitaux de Paris, Necker-Enfants Malades Hospital and Pasteur Institut, Paris, France; and St. Giles Laboratory of Human Genetics of Infectious Diseases (JLC), Rockefeller Branch, The Rockefeller University, New York, New York, United States.

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680355PMC
http://dx.doi.org/10.1097/MD.0b013e31825f95b9DOI Listing
July 2012

Kidney transplant with multiple renal artery grafts from deceased donors: are long-term graft and patient survival compromised?

Prog Transplant 2012 Mar;22(1):102-9

University François Rabelais, Tours, France.

Background: Kidneys with multiple arteries are often transplanted. However, the long-term outcome of such kidneys recovered exclusively from deceased donors is not clear.

Objective: To determine whether use of renal grafts with multiple arteries affects long-term graft survival and function.

Methods: The outcomes of 259 consecutive kidney transplants between 1996 and 2000 were retrospectively reviewed. Patients were divided into 2 groups, multiple renal artery graft recipients (n = 70) and single renal artery graft recipients (n = 189). Short-term complications and long-term outcomes (survival rates, blood pressure after transplant, creatinine clearance, and proteinuria levels at 1, 3, 5, and 7 years after transplant) were compared between the 2 groups.

Results: Early vascular complications were more common (P = .02) in multiple artery graft recipients (18.6%) than in single artery graft recipients (7.9%), mainly because of occlusion of a polar artery in grafts with multiple renal arteries (7.1%). Urologic complications were no more frequent in one group than in the other (5.7% vs 5.3%; P = .89). The 2 groups did not differ significantly (P = .33) in long-term graft survival, with a median follow-up of 9.05 years (range, 0.1-12.7 years). Mean (SD) for creatinine clearance (59.4 [22.6] vs 55.9 [20.3] mL/min; P = .47), proteinuria (0.77 [2.1] vs 0.4 [0.8] g/24 h; P = .19), and systolic blood pressure (133.6 [14.5] vs 133.7 [17.5] mm Hg; P = .85) did not differ significantly between the 2 groups 7 years after transplant.

Conclusions: Kidney transplant with grafts containing multiple renal arteries rather than grafts with a single renal artery does not significantly influence patient and graft outcomes.
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http://dx.doi.org/10.7182/pit2012992DOI Listing
March 2012