Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion.: Apoptosis and regulatory T cells

International audienceApoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover

In Situ-Targeting of Dendritic Cells with Donor-Derived Apoptotic Cells Restrains Indirect Allorecognition and Ameliorates Allograft Vasculopathy

Chronic allograft vasculopathy (CAV) is an atheromatous-like lesion that affects vessels of transplanted organs. It is a component of chronic rejection that conventional immuno-suppression fails to prevent, and is a major cause of graft loss. Indirect allo-recognition through T cells and allo-Abs are critical during CAV pathogenesis. We tested whether the indirect allo-response and its impact on CAV is down-regulated by in situ-delivery of donor Ags to recipient's dendritic cells (DCs) in lymphoid organs in a pro-tolerogenic fashion, through administration of donor splenocytes undergoing early apoptosis. Following systemic injection, donor apoptotic cells were internalized by splenic CD11chi CD8α+ and CD8− DCs, but not by CD11cint plasmacytoid DCs. Those DCs that phagocytosed apoptotic cells in vivo remained quiescent, resisted ex vivo-maturation, and presented allo-Ag for up to 3 days. Administration of donor apoptotic splenocytes, unlike cells alive, (i) promoted deletion, FoxP3 expression and IL-10 secretion, and decreased IFN-γ-release in indirect pathway CD4 T cells; and (ii) reduced cross-priming of anti-donor CD8 T cells in vivo. Targeting recipient's DCs with donor apoptotic cells reduced significantly CAV in a fully-mismatched aortic allograft model. The effect was donor specific, dependent on the physical characteristics of the apoptotic cells, and was associated to down-regulation of the indirect type-1 T cell allo-response and secretion of allo-Abs, when compared to recipients treated with donor cells alive or necrotic. Down-regulation of indirect allo-recognition through in situ-delivery of donor-Ag to recipient's quiescent DCs constitutes a promising strategy to prevent/ameliorate indirect allorecognition and CAV

Apoptotic cell-based therapies against transplant rejection: role of recipient’s dendritic cells

One of the ultimate goals in transplantation is to develop novel therapeutic methods for induction of donor-specific tolerance to reduce the side effects caused by the generalized immunosuppression associated to the currently used pharmacologic regimens. Interaction or phagocytosis of cells in early apoptosis exerts potent anti-inflammatory and immunosuppressive effects on antigen (Ag)-presenting cells (APC) like dendritic cells (DC) and macrophages. This observation led to the idea that apoptotic cell-based therapies could be employed to deliver donor-Ag in combination with regulatory signals to recipient’s APC as therapeutic approach to restrain the anti-donor response. This review describes the multiple mechanisms by which apoptotic cells down-modulate the immuno-stimulatory and pro-inflammatory functions of DC and macrophages, and the role of the interaction between apoptotic cells and APC in self-tolerance and in apoptotic cell-based therapies to prevent/treat allograft rejection and graft-versus-host disease in murine experimental systems and in humans. It also explores the role that in vivo-generated apoptotic cells could have in the beneficial effects of extracorporeal photopheresis, donor-specific transfusion, and tolerogenic DC-based therapies in transplantation

Insuffisance rénale chronique et transplantation rénale

International audienceOBJECTIVES:To report epidemiology and characteristics of end-stage renal disease (ESRD) patients and renal transplant candidates, and to evaluate access to waiting list and results of renal transplantation.MATERIAL AND METHODS:An exhaustive systematic review of the scientific literature was performed in the Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of the following keywords: "chronic kidney disease, epidemiology, kidney transplantation, cost, survival, graft, brain death, cardiac arrest, access, allocation". French legal documents have been reviewed using the government portal (http://www.legifrance.gouv.fr). Articles were selected according to methods, language of publication and relevance. The reference lists were used to identify additional historical studies of interest. Both prospective and retrospective series, in French and English, as well as review articles and recommendations were selected. In addition, French national transplant and health agencies (http://www.agence-biomedecine.fr and http://www.has-sante.fr) databases were screened using identical keywords. A total of 3234 articles, 6 official reports and 3 newspaper articles were identified; after careful selection 99 publications were eligible for our review.RESULTS:The increasing prevalence of chronic kidney disease (CKD) leads to worsen organ shortage. Renal transplantation remains the best treatment option for ESRD, providing recipients with an increased survival and quality of life, at lower costs than other renal replacement therapies. The never-ending lengthening of the waiting list raises issues regarding treatment strategies and candidates' selection, and underlines the limits of organ sharing without additional source of kidneys available for transplantation.CONCLUSION:Allocation policies aim to reduce medical or geographical disparities regarding enrollment on a waiting list or access to an allotransplant

Troubles du bas appareil urinaire et de la statique pelvienne chez les candidats et receveurs d’une transplantation rénale

International audienceOBJECTIVES:To describe lower urinary tract symptoms (LUTS) and their management in renal transplant candidates and recipients.MATERIAL AND METHODS:Relevant publications were identified through Medline (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) database using the following keywords, alone or in association: "transplantation", "prostate hyperplasia", "transurethral resection of prostate", "urinary incontinence", "LUTS", "pelvic floor dysfunction". Articles were selected according to methods, language of publication and relevance. The reference lists were used to identify additional historical studies of interest. Both prospective and retrospective series, in French and English, as well as review articles and case reports were selected. In addition, French national transplant and health agencies (http://www.agence-biomedecine.fr and http://www.has-sante.fr) databases were screened using identical keywords. A total of 991 articles were analyzed and after careful selection, 47 publications were eligible for our review.RESULTS:Reduction of bladder capacity, due to dialysis and anuria, is correlated with dialysis duration. This reduction is reversible after renal transplantation and does not seem to put renal transplant recipients at risk for medical complications. Transplant procedure generally allows restoration of bladder maximal output, normal bladder capacity and compliance. Medical treatment of LUTS related to prostate hyperplasia (BPH) includes alpha-blockers and finasteride. Silodosin and dutasteride have not been evaluated in that setting. Antimuscarinics may be used with caution, and favor the use of solifenacin at 5mg per day. Surgical treatment of BPH requires a preserved urine output, otherwise must be delayed after transplantation; it may thus be performed safely in the early postoperative course. Botulinum toxin injections and surgical treatment of stress incontinence and prolapse are barely reported in this population.CONCLUSION:Precise assessment and optimal management of LUTS in renal transplant candidates and recipients are critical to improve quality of life and to preserve allotransplant function. Literature data lack evidence to propose robust recommendations. However, knowledge of reported specificities in this peculiar setting is mandatory for urologists to provide patients with finest options and optimal treatment timing

Histoire chirurgicale de la transplantation rénale

International audienceOBJECTIVES:To perform a state of the art about the history of kidney transplantation.MATERIAL AND METHODS:An exhaustive systematic review of the scientific literature was performed in the Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of the following keywords (MESH): kidney transplantation, history, vascular anastomosis.RESULTS:From the first vascular ligations to the discovery of ciclosporin, the history of organ transplantation was made of surgical bets and medical discoveries, such as blood group, HLA-system, immunity, etc. The audacity of some surgeons led to the onset of renal transplantation as the treatment of choice for end stage renal disease.CONCLUSION:This article aims to describe the first surgical methods for vascular anastomosis and renal transplantation. Through a comprehensive search within the archives of the French National Library, the authors provide a precise description of the first renal transplantations performed, the technique that have been used and their authors

Complications chirurgicales de la transplantation rénale

International audienceOBJECTIVE:To report the nature, incidence, diagnosis and treatment options of surgical complications after renal transplantation.MATERIAL AND METHODS:Relevant publications were identified through Medline (http://www.ncbi.nlm.nih.gov/) and Embase (http://www.embase.com/) database from 1960 to 2016 using the following keywords "fistula; lymphocele; stricture; thrombosis", in association with "renal transplantation" in Title/Abstract field. Articles were selected according to methods, language of publication and relevance. A total of 7618 articles were identified including specifically 981 for vascular complications, 1016 for urologic complications and 239 for lymphocele; after careful selection 190 publications were eligible for our review.RESULTS:Surgical complications occur in 1 to 30% of renal transplantations while being incompletely reported without consensual management. Angioplasty techniques led to a significant improvement of short- and long-term vascular complications outcome. Risk factors for transplant thrombosis are a right allotransplant, multiple renal arteries or vasculopathy in the donor, diabetes, arterial disease or thrombophilia in the recipient and hemodynamic changes during procedure. Urinary complications and lymphocele significantly impair overall outcome and recipients quality of life with no demonstrated impact on allotransplant survival. Immediate or salvage pelvi-ureterostomy is a main treatment option for ureteral strictures and fistula.CONCLUSION:Prevention of surgical complications following renal transplantation relies on careful allotransplant preparation and strict respect of surgical best practices. Increasing comorbidities in recipients as well as marginal donors are significant limits for the improvement of post-transplant surgical outcome

La transplantation rénale en 2046 : avenir et perspectives

International audienceOBJECTIVES:To report major findings that may build the future of kidney transplantation.MATERIAL AND METHODS:Relevant publications were identified through Medline (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) database from 1960 to 2016 using the following keywords, in association, "bio-engineering; heterotransplantation; immunomodulation; kidney; regenerative medicine; xenotransplantation". Articles were selected according to methods, language of publication and relevance. A total of 5621 articles were identified including 2264 for xenotransplantation, 1058 for regenerative medicine and 2299 for immunomodulation; after careful selection, 86 publications were eligible for our review.RESULTS:Despite genetic constructs, xenotransplantation faces the inevitable obstacle of species barrier. Uncertainty regarding xenograft acceptance by recipients as well as ethical considerations due to the debatable utilization of animal lives, are major limits for its future. Regenerative medicine and tridimensional bioprinting allow successful implantation of organs. Bioengineering, using decellularized tissue matrices or synthetic scaffold, seeded with pluripotent cells and assembled using bioreactors, provide exciting results but remain far for reconstituting renal complexity and vascular patency. Immune tolerance may be achieved through a tough initial T-cell depletion or a combined haplo-identical bone marrow transplant leading to lymphohematopoietic chimerism.CONCLUSION:Current researches aim to increase the pool of organs available for transplantation (xenotransplants and bio-artificial kidneys) and to increase allograft survival through the induction of immune tolerance. Reported results suggest the onset of a thrilling new era for renal transplantation providing end-stage renal disease-patients with an improved survival and quality of life

La transplantation rénale et ses défis

International audienceOBJECTIVES:To describe kidney transplantation surgical techniques and to propose strategies in high-risk recipients.MATERIAL AND METHODS:Relevant publications were identified through Medline (http://www.ncbi.nlm.nih.gov/) and Embase (http://www.embase.com/) database using the following keywords, alone or in association, "renal transplantation; peripheral arterial disease; obesity; third and fourth transplantation; robotic-assisted kidney transplant; anticoagulant therapy; dual kidney transplant". Articles were selected according to methods, language of publication and relevance. The reference lists were used to identify additional historical studies of interest. Both prospective and retrospective series, in French and English, as well as review articles and case-reports were selected. A total of 1949 articles were analyzed for arterial disease and anticoagulant therapy, 1083 for obesity, 663 for dual kidney transplants, 458 for third and subsequent procedures and 84 for robotic-assisted kidney transplantation. After careful selection, 304 publications were eligible for our review.RESULTS:Surgical assessment of future recipients is a pivotal step to anticipate technical difficulties, to interrupt clopidogrel or direct oral anticoagulants and to propose a revascularization procedure when necessary. Lack of data regarding obese recipients does not allow us to conclude about best surgical care or optimal timing but suggest that an early global management of obesity in chronic kidney disease patients is mandatory to improve access to a successful transplantation. In neurologic bladder and congenital anomalies, urodynamics and bladder function must be assessed prior to the onset of oliguria to intend an early treatment. Urinary diversion may be performed prior to or after transplantation with similar survival outcome and comparable rates of infections. Because of a rigorous selection of donors, the French dual kidney transplant program provides satisfactory outcomes, but fails in convincing surgical teams nationwide. Third and subsequent transplant procedures remain a surgical and immunological challenge, with an increased morbidity and a moderate decline in transplant survival only when donors are extended criteria' with extensive duration of waiting time between procedures. Robotic-assisted kidney transplantation is a recent technique requiring methodical evaluation.CONCLUSION:Kidney transplantation in challenging recipients implies a global understanding of patients' prognosis and benefits versus dialysis, in the context of the attribution of a valuable resource awaited by other patients on waiting list