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Contains fulltext : 229465.pdf (Publisher’s version ) (Closed access) BACKGROUND: Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen during preservation might improve post-transplant outcomes, particularly for kidneys subjected to greater degrees of preservation injury. This study aimed to investigate whether supplemental oxygen during hypothermic machine perfusion (HMP) could improve the outcome of kidneys donated after circulatory death. METHODS: This randomised, double-blind, paired, phase 3 trial was done in 19 European transplant centres. Kidney pairs from donors aged 50 years or older, donated after circulatory death, were eligible if both kidneys were transplanted into two different recipients. One kidney from each donor was randomly assigned using permuted blocks to oxygenated hypothermic machine perfusion (HMPO(2)), the other to HMP without oxygenation. Perfusion was maintained from organ retrieval to implantation. The primary outcome was 12-month estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation in pairs of donated kidneys in which both transplanted kidneys were functioning at the end of follow-up. Safety outcomes were reported for all transplanted kidneys. Intention-to-treat analyses were done. This trial is registered with the ISRCTN Registry, ISRCTN32967929, and is now closed. FINDINGS: Between March 15, 2015, and April 11, 2017, 197 kidney pairs were randomised with 106 pairs transplanted into eligible recipients. 23 kidney pairs were excluded from the primary analysis because of kidney failure or patient death. Mean eGFR at 12 months was 50·5 mL/min per 1·73 m(2) (SD 19·3) in the HMPO(2) group versus 46·7 mL/min per 1·73m(2) (17·1) in HMP (mean difference 3·7 mL/min per 1·73m(2), 95% CI -1·0 to 8·4; p=0·12). Fewer severe complications (Clavien-Dindo grade IIIb or more) were reported in the HMPO(2) group (46 of 417, 11%, 95% CI 8% to 14%) than in the HMP group (76 of 474, 16%, 13% to 20%; p=0·032). Graft failure was lower with HMPO(2) (three [3%] of 106) compared with HMP (11 [10%] of 106; hazard ratio 0·27, 95% CI 0·07 to 0·95; p=0·028). INTERPRETATION: HMPO(2) of kidneys donated after circulatory death is safe and reduces post-transplant complications (grade IIIb or more). The 12-month difference in eGFR between the HMPO(2) and HMP groups was not significant when both kidneys from the same donor were still functioning 1-year post-transplant, but potential beneficial effects of HMPO(2) were suggested by analysis of secondary outcomes. FUNDING: European Commission 7th Framework Programme.

BACKGROUND: Changes in recipient and donor factors have reopened the question of survival benefits of kidney transplantation versus dialysis. METHODS: We analysed survival among 3808 adult Belgian patients waitlisted for a first deceased donor kidney transplant from 2000 to 2012. The primary outcome was mortality during the median waiting time plus 3 years of follow-up after transplantation or with continued dialysis. Outcomes were analysed separately for standard criteria donor (SCD) and expanded criteria donor (ECD) kidney transplants. We adjusted survival analyses for recipient age (20-44, 45-64 and ≥65 years), sex and diabetes as the primary renal disease. RESULTS: Among patients ≥65 years of age, only SCD transplantation provided a significant survival benefit compared with dialysis, with a mortality of 16.3% [95% confidence interval (CI) 13.2-19.9] with SCD transplantation, 20.5% (95% CI 16.1-24.6) with ECD transplantation and 24.6% (95% CI 19.4-29.5) with continued dialysis. Relative mortality risk was increased in the first months after transplantation compared with dialysis, with equivalent risk levels reached earlier with SCD than ECD transplantation in all age groups. CONCLUSIONS: The results of this study suggest that older patients might gain a survival benefit with SCD transplantation versus dialysis, but any survival benefit with ECD transplantation versus dialysis may be small., SCOPUS: ar.j, info:eu-repo/semantics/published

Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). IRI-induced AKI releases proinflammatory cytokines (e.g. IL-1β, TNF-α, IL-6) that induce a systemic inflammatory response, resulting in proinflammatory cells recruitment and remote organ damage. AKI is associated with poor outcomes, particularly when extrarenal complications or distant organ injuries occur. Acute lung injury (ALI) is a major remote organ dysfunction associated with AKI. Hence, kidney-lung cross-talk remains a clinical challenge, especially in critically ill population. The stress-responsive enzyme, heme oxygenase-1 (HO-1) is largely known to protect against renal IRI and may be preventively induced using hemin prior to renal insult. However, the use of hemin-induced HO-1 to prevent AKI-induced ALI remains poorly investigated. Mice received an intraperitoneal injection of hemin or sterile saline 1 day prior to surgery. Twenty-four hours later, mice underwent bilateral renal IRI for 26 min or sham surgery. After 4 or 24 h of reperfusion, mice were sacrificed. Hemin-induced HO-1 improved renal outcomes after IRI (i.e. fewer renal damage, renal inflammation, and oxidative stress). This protective effect was associated with a dampened systemic inflammation (i.e. IL-6 and KC). Subsequently, mitigated lung inflammation was found in hemin-treated mice (i.e. neutrophils influx and lung KC). The present study demonstrates that hemin-induced HO-1 controls the magnitude of renal IRI and the subsequent AKI-induced ALI. Therefore, targeting HO-1 represents a promising approach to prevent the impact of renal IRI on distant organs, such as lung., SCOPUS: ar.j, info:eu-repo/semantics/published

Graft-versus-host disease (GVHD) remains a major clinical drawback of allogeneic hematopoietic stem cell transplantation (HSCT). Here, we investigated how the stress responsive heme catabolizing enzyme heme oxygenase-1 (HO-1, encoded by HMOX1) regulates GVHD in response to allogeneic hematopoietic stem cell transplantation in mice and humans. We found that deletion of the Hmox1 allele, specifically in the myeloid compartment of mouse donor bone marrow, promotes the development of aggressive GVHD after allogeneic transplantation. The mechanism driving GVHD in mice transplanted with allogeneic bone marrow lacking HO-1 expression in the myeloid compartment involves enhanced T cell alloreactivity. The clinical relevance of these observations was validated in two independent cohorts of HSCT patients. Individuals transplanted with hematopoietic stem cells from donors carrying a long homozygous (GT)n repeat polymorphism (L/L) in the HMOX1 promoter, which is associated with lower HO-1 expression, were at higher risk of developing severe acute GVHD as compared to donors carrying a short (GT)n repeat (S/L or S/S) polymorphism associated with higher HO-1 expression. In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human HMOX1 (GT)n microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. Donor-derived myeloid HO-1 constitutes a potential therapeutic target for HSCT patients and large-scale prospective studies in HSCT patients are necessary to validate the HO-1 L/L genotype as an independent risk factor for developing severe acute GVHD., SCOPUS: ar.j, info:eu-repo/semantics/published

Many transplant physicians screen for and treat asymptomatic bacteriuria (ASB) during post-kidney-transplant surveillance. We investigated whether antibiotics are effective in reducing the occurrence of symptomatic urinary tract infection (UTI) in kidney transplant recipients with ASB., info:eu-repo/semantics/published

Background and Aims Older studies have shown a survival benefit with kidney transplantation compared to dialysis, even for patients older than 60 years. However, due to important evolutions such as older recipient age and the use of less-than-optimal quality donors, it is unclear if the survival benefit with transplantation still holds true nowadays. Method Patient survival was analyzed for 3808 Belgian patients waitlisted for a first deceased donor kidney transplant between 2000 to 2012. Patients were divided into age categories (20-44y, 45-64y, ≥65y). Primary outcome was the comparison of mortality during median waiting time plus 3 years follow-up, either after transplantation or when remaining on dialysis. Outcomes were analyzed separately for those receiving a standard criteria donor (SCD) or an expanded criteria donor (ECD) transplant. The survival analyses were adjusted for age, sex and primary renal disease. Results Among patients ≥ 65 years old, only SCD transplantation provided a significant survival benefit compared to dialysis: mortality was 16.3 % (95 % CI: 13.2–19.9 %) with SCD transplantation, 20.5 % (16.1–24.6 %) with ECD transplantation, and 24.6 % (19.5–29.5 %) when remaining on dialysis. Relative mortality risk was increased in the first months after transplantation compared to dialysis, with equal risk levels being reached earlier for SCD than ECD transplantations in all age groups. Conclusion This study suggests that older patients have a survival benefit with SCD transplantation versus dialysis, but the survival benefit with ECD transplantation versus dialysis may be small or non-existent.

Acute kidney injury (AKI) is a major public health concern, which is contributing to serious hospital complications, chronic kidney disease (CKD) and even death. Renal ischemia-reperfusion injury (IRI) remains a leading cause of AKI. The stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against renal IRI and may be preventively induced using hemin prior to renal insult. This HO-1 induction pathway called hemin preconditioning is largely known to be effective. Therefore, HO-1 might be an interesting therapeutic target in case of predictable AKI (e.g. partial nephrectomy or renal transplantation). However, the use of hemin to mitigate established AKI remains poorly characterized. Mice underwent bilateral renal IRI for 26 min or sham surgery. After surgical procedure, animals were injected either with hemin (5 mg/kg) or vehicle. Twenty-four hours later, mice were sacrificed. Despite strong HO-1 induction, hemin-treated mice exhibited significant renal damage and oxidative stress as compared to vehicle-treated mice. Interestingly, higher dose of hemin is associated with more severe IRI-induced AKI in a dose-dependent relation. To determine whether hemin preconditioning remains efficient to dampen postoperative hemin-amplified IRI-induced AKI, we pretreated mice either with hemin (5 mg/kg) or vehicle 24 h prior to surgical procedure. Then, all mice (hemin- and vehicle-pretreated) received postoperative injection of hemin (5 mg/kg) to amplify IRI-induced AKI. In comparison to vehicle, prior administration of hemin to renal IRI mitigated hemin-amplified IRI-induced AKI as attested by fewer renal damage, inflammation and oxidative stress. In conclusion, hemin may have a dual effect on renal IRI, protective or deleterious, depending on the timing of its administration.

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

BACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that in vitro cell-based assays are needed to improve risk assessments before transplant.

Checkpoint inhibitors (CPIs) provide impressive response rates among immunocompetent patients with various solid tumors. So far, organ transplant recipients have been excluded from clinical studies due to the putative risk of allograft rejection however 48 cases of liver and renal transplant patients treated with CPI were already described in literature., SCOPUS: ar.j, info:eu-repo/semantics/published

Urinary tract infection is the most common infection among kidney transplant recipients (KTRs). Many transplant physicians fear that host compromise will allow low-virulence strains to cause pyelonephritis in KTRs, so they often treat asymptomatic bacteriuria with antibiotics. Identification of the host/microbe factors that determine the clinical presentation (i.e. pyelonephritis versus asymptomatic bacteriuria) once an Escherichia coli strain enters a KTRs bladder could inform management decisions., info:eu-repo/semantics/published

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication and is associated with the poorest outcomes. Therefore, early prediction of CSA-AKI remains a major issue. Severity scores such as the STS score could estimate the risk of AKI preoperatively. The main objective of this study was to evaluate the risk factors of on-pump CSA-AKI and to assess the performance of the STS score in order to predict CSA-AKI.We identified 252 patients with on-pump cardiac surgery, and the STS score was defined retrospectively.AKI occurred in 14.6% (n = 37/252) of patients and renal replacement therapy was required in 21.6% of AKI (n = 8/37). CSA-AKI was associated with 35.1% in-hospital mortality (vs. 1.4%) and nearly doubled length of stay (14.5 vs. 8.0 d). The risk of CSA-AKI was mainly determined by preoperative morbidities such as chronic kidney disease, peripheral vascular disease, and severe congestive heart failure. Long cardio-pulmonary bypass time was also a determinant. CSA-AKI + patients exhibited higher STS renal risk (5.6% vs. 2.0%; p 0.0001), resulting in a good discrimination between AKI + and AKI - patients (area under curve [AUC] 0.80). Interestingly, a basal renal function ≤55 ml/min/1.73mOn-pump CSA-AKI was observed in nearly 15% of cases and was associated with poorer outcomes. Interestingly, the risk of CSA-AKI could be estimated preoperatively, thanks to the basal renal function, which exhibited an equal performance to the STS score.

Background Therapeutic drug monitoring of mycophenolic acid (MPA) is usually performed with a limited sampling strategy (LSS), which relies on a limited number of blood samples and subsequent extrapolation of the global exposure to MPA. LSS is usually performed successfully with mycophenolate mofetil (MMF), but data on enteric-coated mycophenolate sodium (EC-MPS) are scarce. Here, we evaluated the feasibility of 6-h LSS therapeutic drug monitoring with EC-MPS compared with MMF monitoring among kidney transplant recipients. Methods Sixty-two patients who received EC-MPS during the first 6 months of transplantation were compared with a matched group of 64 MMF-treated kidney transplant recipients. The area under the curve (AUC) was computed by LSS using multiple concentration time points (0, 1, 2, 3 and 6 h post-dose) and a trapezoidal rule. Patients had MPA therapeutic drug monitoring performed on two occasions, one within 2 weeks and the second after 3-4 months of transplantation. Results EC-MPS monitoring and MMF therapeutic drug monitoring were not interpretable in 34.5% (n = 40/116) and 1.8% (n = 2/112) of patients, respectively {relative risk [RR] 19.3 [95% confidence interval (CI) 4.8-78.0]; P < 0.0001}. The main cause of abnormal EC-MPS therapeutic drug monitoring was delayed absorption of both the previous evening and the morning dose, resulting in MPA plasma levels before the next morning dose being higher than MPA plasma levels measured at 1, 2 and 3 h after taking EC-MPS. Cyclosporin in association with MMF significantly increased the risk of low AUC values (30% during the first 6 months of renal transplantation. Delayed pharmacokinetics was the main reason. In contrast, the risk of therapeutic drug monitoring failure was substantially lower with MMF., SCOPUS: ar.j, info:eu-repo/semantics/published

The clinical practice of vascularized composite allotransplantation (VCA) has been limited by the potential side effects of chronic immunosuppression. Studies using rodent models have been useful for dissecting mechanisms underlying immunological events induced by VCA and for developing protocols such as mixed chimerism for tolerance induction. Mouse models of VCA have great advantages over rat and other rodents with regard to dissection of immunologic mechanisms; however, the microsurgical revascularization procedures that are required are much more difficult. Here we review recent advances in surgical and immunological methods for successful VCA in the mouse model.

Polyomavirus (PV) is a major cause of kidney graft disease. Monitoring by polymerase chain reaction (PCR) on blood is currently recommended. In order to avoid irreversible lesions, we investigated the clinical impact of preemptive reduction of immunosuppression (IS) in kidney transplant recipients (KTR) upon detection of high urinary PV (Upv) load, including BK virus and JC virus.From 2000 to 2011, in our single center, 789 consecutive KTR were distributed into 4 groups, according to the maximal Upv levels (by PCR) during the first year and the therapeutic option: (A) Upv10The preemptive reduction of IS (group Ca) increased patient survival as compared with all other groups (P.05), did not modify graft function, and increased graft survival vs group A (risk ratio: 5.7, confidence interval: 1.8-18.1, P=.003). Differences for risk factors are as follows (groups Ca vs A): incidence of human leukocyte antigen (HLA) immunization (5% panel reactive antibodies): 3% vs 8% (P=.05), number of HLA mismatches: 2.7 vs 2.5 (P=.049), and incidence of acute rejection: 9.8% vs 24.2% (P=.005). PV-associated nephropathy occurred only in group Ca (2% of total grafts) without effect on patient or graft outcome.The reduction of IS in patients with high Upv loads is beneficial for patient survival and does not affect graft survival or graft function.

Background. Several studies suggest that the introduction of tacrolimus (TRL), mycophenolic acid (MPA) and interleukin 2 receptor antibodies (IL2Ra) as single drugs more than a decade ago has not increased the risk of malignancy after renal transplantation. However, only limited data are available on their carcinogenic effects when used in combination as a potent immunosuppressive regimen. Methods. A retrospective single-centre cohort study on 929 adult renal transplant recipients. Investigation of the effect of two consecutive immunosuppressive regimens [1993–98, N ¼ 405, anti-lymphocyte antibodies, cyclosporine and azathioprine (AZA); 1999–2007, N ¼ 524, predominantly IL2Ra, TRL and MPA] on the incidence rate of skin cancer, solid tumours and post-transplant lymphoproliferative disease (PTLD). Results. In total, 365 malignancies developed among 113 patients. As compared to the previous cyclosporine and AZA-based immunosuppression, the introduction of the new immunosuppressive regimen did not increase the incidence rate of skin cancer [rate ratio 0.84; 95% confidence interval (CI) 0.48–1.46], solid tumours (0.89; 95% CI 0.46–1.67) and PTLD (0.82; 95% CI 0.28–2.21). Patients treated with the more recent regimens less frequently developed multiple skin cancers and invasive squamous cell cancer. Skin cancer after transplantation was strongly associated with the development of solid tumours (odds ratio 5.2; P < 0.0001). The introduction of the new immunosuppressive drugs reduced the incidence of first year acute rejection from 34.8 to 13.2% (P < 0.0001). Conclusion. Although significantly more efficient in the prevention of acute rejection, the introduction of TRL, MPA and IL2Ra-based immunosuppression after kidney transplantation was not associated with an increased incidence of skin cancer, solid tumours or PTLD.

Background Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. Methods Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many operationally tolerant patients (TOL; defined as having a serum creatinine

Background. Although numerous risk factors for delayed graft function (DGF) have been identified, the role of ischemia-reperfusion injury and acute rejection episodes (ARE) occurring during the DGF period is ill-defined and DGF impact on patient and graft outcome remains controversial. Methods. From 1983 to 2014, 1784 kidney-only transplantations from deceased donors were studied. Classical risk factors for DGF along with two novel ones, recipient's perioperative saline loading and residual diuresis, were analyzed by logistic regression and receiver operating characteristic (ROC) curves. Results. Along with other risk factors, absence of perioperative saline loading increases acute rejection incidence (OR = 1.9 [1.2-2.9]). Moreover, we observed two novel risk factors for DGF: patient's residual diuresis ≤500 mL/d (OR = 2.3 [1.6-3.5]) and absence of perioperative saline loading (OR = 3.3 [2.0-5.4]). Area under the curve of the ROC curve (0.77 [0.74-0.81]) shows an excellent discriminant power of our model, irrespective of rejection. DGF does not influence patient survival (P = 0.54). However, graft survival is decreased only when rejection was associated with DGF (P < 0.001). Conclusions. Perioperative saline loading efficiently prevents ischemia-reperfusion injury, which is the predominant factor inducing DGF. DGF per se has no influence on patient and graft outcome. Its incidence is currently close to 5% in our centre., info:eu-repo/semantics/published

Rapid, simple, and reliable assays to monitor allogeneic responses are essential for the safe development of novel protocols of tailored immunosuppression. Herein, we describe a real-time polymerase chain reaction method based on interleukin-2 and interferon-gamma mRNA quantification upon stimulation of whole blood with allogeneic T cell-depleted peripheral blood mononuclear cells. The technique requires only small blood volumes and results can be obtained within 48 hours. Data obtained in a liver transplant patient receiving a tolerance induction protocol based on the infusion of donor-type hematopoietic stem cells suggest that this rapid whole blood mixed lymphocyte reaction assay could be valuable for the monitoring of patients undergoing solid organ or hematopoietic stem cell transplantation.

Because rejection of allografts is primarily caused by T and B lymphocyte responses to allogeneic histocompatibility molecules, the role of innate immunity in organ transplant rejection is often overlooked. However, the very first damages to vascularized organ allografts are caused by ischemia-reperfusion, an inflammatory reaction involving activation of vascular endothelial cells and release of neutrophil chemoattractants. Herein, we review experimental observations suggesting that the early neutrophil influx in organ transplants favors T cell-mediated rejection.

In recent years, regulatory T (Treg) cells have reached centre-stage in immune tolerance research. A role for Treg cells in preventing autoimmunity or generating transplantation tolerance is now undisputed. However, in spite of a surge in publications dedicated to Treg cells, surprisingly little is known about their induction, biology and mechanisms of action. In this Opinion, we discuss the facts and the controversies regarding their role in transplantation tolerance. We suggest that peripheral generation of Treg cells, crucial for the generation of dominant transplantation tolerance, might be a consequence of sustained suboptimal antigenic stimulation, and that transforming growth factor-β (TGF-β) might contribute to this process by increasing the threshold for T-cell activation. © 2004 Elsevier Ltd. All rights reserved.

Allograft rejection results from a complex process involving both the innate and acquired immune systems. The innate immune system predominates in the early phase of the allogeneic response, during which chemokines and cell adhesion play essential roles, not only for leukocyte migration into the graft but also for facilitating dendritic and T-cell trafficking between lymph nodes and the transplant. This results in a specific and acquired alloimmune response mediated by T cells. Subsequently, T cells and cells from innate immune system function synergistically to reject the allograft through nonexclusive pathways, including contact-dependent T cell cytotoxicity, granulocyte activation by either Th1 or Th2 derived cytokines, NK cell activation, alloantibody production, and complement activation. Blockade of individual pathways generally does not prevent allograft rejection, and long-term allograft survival is achieved only after simultaneous blockade of several of them. In this review, we explore each of these pathways and discuss the experimental evidence highlighting their roles in allograft rejection.

Eosinophils release inflammatory mediators and cationic proteins that are instrumental in the pathogenesis of allergic diseases such as bronchial asthma. Here, we review experimental observations indicating that eosinophils are also involved in the rejection of allografts. We propose that their role as effectors of transplant damage becomes crucial when classical pathways of rejection are inhibited and T helper 2 (Th2) cells dominate the alloimmune response.

BACKGROUND: Patients undergoing kidney transplantation are sometimes being treated with antiplatelet agents such as ticlopidine or clopidogrel. Some teams refuse to wait-list these patients for fear of bleeding during transplant surgery. METHODS: We retrospectively reviewed the records of 702 adult patients with a kidney transplant alone between 2000 and 2010. Nineteen (2.7%) patients were taking clopidogrel or ticlopidine when called in for transplantation. Furthermore, 10 of these 19 patients were also taking low-dose aspirin (ASA). We compared the risk of bleeding peri- and postoperatively, and the occurrence of cardiovascular complications within 30 days after renal transplantation between 19 cases and 39 controls randomly selected within the cohort. RESULTS: Platelets were administered to 7 cases (37%) versus 0 controls (P

C57BL/6 mice injected with the 145-2C11 anti-CD3 mAb and grafted with MHC class II disparate bm12 skin develop a chronic rejection characterized by interstitial dermal fibrosis, a marked eosinophil infiltrate, and an obliterative intimal vasculopathy. Because these changes occur in the absence of alloreactive antibodies, we examined the contribution of cytokines in their pathogenesis. Chronically rejected grafts showed a marked accumulation of both IL-4 and IL-5 mRNA. Mixed lymphocyte reaction experiments established that mice undergoing chronic rejection were primed for IL-4, IL-5, and IL-10 secretion. In vivo administration of anti-IL-4 mAb completely prevented allograft vasculopathy as well as graft eosinophil infiltration and dermal fibrosis. Injection of anti-IL-5 mAb or the use of IL-5-deficient mice as recipients also resulted in the lack of eosinophil infiltration or dermal fibrosis, but these mice did develop allograft vasculopathy. Administration of anti-IL-10 mAb did not influence any histologic parameter of chronic rejection. Thus, in this model, IL-4- and IL-5-mediated tissue allograft eosinophil infiltration is associated with interstitial fibrosis. IL-4, but not eosinophils, is also required for the development of obliterative graft arteriolopathy.

Background. We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin. Methods. LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells. Results. Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8(+) T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (VA/HPRT ratio) and gradually enhanced anti-cytomegalovirus and anti-Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-gamma and interleukin (IL)-17, increased intragraft expression of IFN-gamma mRNA, and significant CD8(+) T-cell infiltrates colocalizing with IL-17(+) cells. Conclusion. High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory-type CD8(+) T cells and increased levels of IFN-gamma and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell-depleting induction.

AKI encompasses a large spectrum of pathophysiological processes starting from the early reversible proximal tubular lesion to the definite loss of glomerular filtration and even death. Even discrete AKI ( i.e. , ≥0.3 mg/dl increase in serum creatinine in humans) has been reported to be associated

The recent interest for Th17 cells immediately raised questions about their possible involvement in allogeneic processes. Indeed, IL-17-producing innate immune cells and Th17 cells have now been related to allograft rejection and ischemia-reperfusion injury in clinical settings and in experimental models. Some of them clearly established a link between the presence of these cells and the development of long-term graft dysfunction. A pivotal role of a Th17-mediated pathway in transplant damage has been demonstrated independently of MHC disparities with T cells recognizing either autoantigen or minor transplantation antigen. The ambiguous relationship between regulatory T cells (Treg) and Th17 cells also complicates Treg-based therapy. Herein, we briefly discuss recent studies reporting Th17 and IL-17 involvements in allograft rejection processes.

SCOPUS: no.j, info:eu-repo/semantics/published

Background. Advagraf is a slow release form of tacrolimus with once-daily formulation. The potential advantages of Advagraf are better adherence and a safer profile by avoiding toxic peak concentrations. In this study, we evaluated the required daily doses of tacrolimus and subsequent blood levels on conversion from Prograf to Advagraf among kidney transplant recipients. Methods. We retrospectively reviewed data from 55 patients for whom a switch from Prograf to Advagraf was identified. Tacrolimus daily doses and concomitant blood levels were analyzed at several time points ranging from 3 months before to 6 months after conversion. Results. We observed a significant increase in tacrolimus daily doses, starting with a dose of 0.063 mg/kg of Prograf, increasing up to 0.081 mg/kg of Advagraf at 6 months (P

Kidney ischemia/reperfusion injury (I/R) is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the alpha7nAChR, as attested by the absence of protection in alpha7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-alpha and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic alpha7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

BACKGROUND: Eosinophils participate in allograft rejection when donor-reactive helper T lymphocytes are T-helper type 2 (Th2)-biased. Whereas the involvement of interleukin (IL)-4 and IL-5 in these forms of rejection is well established, the role of IL-9, another Th2-type cytokine promoting eosinophilia, has not been determined. METHODS: We first used real-time polymerase chain reaction to quantify IL-9 mRNA in rejected allografts in a mouse model of fully mismatched heart transplantation in which recipients were devoid of CD8 T cells and developed a Th2 alloimmune response. We then compared allograft survival in wild-type versus IL-9-deficient mice depleted of CD8 T cells. Finally, we compared the fate of major histocompatibility complex class II-mismatched cardiac transplants from wild-type versus IL-9 transgenic donors to determine the influence of IL-9 overexpression within the graft. RESULTS: The Th2 alloimmune response in CD8-deficient mice was associated with the accumulation of IL-9 mRNA in the rejected graft. In IL-9-deficient recipients depleted of CD8 T cells, eosinophil infiltration of heart allografts did not develop, but rejection still occurred. In the major histocompatibility complex class II disparate model, heart allografts from IL-9 transgenic donors were acutely rejected, whereas grafts from wild-type donors did not develop rejection. Acute rejection of IL-9 transgenic hearts was associated with massive eosinophil infiltration and prevented by neutralization of either IL-4 or IL-5. CONCLUSION: IL-9 is critically involved in heart transplant eosinophilia in conjunction with IL-4 and IL-5., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Allograft rejection results from separate pathways primarily controlled by CD4+ T cells. Refinement of transplantation models together with investigations on rejection occurring despite co-stimulation blockade revealed unexpected pathways involving CD8+ T cells, NK cells and Th2 cytokines. In this minireview, we discuss these non-classical pathways of allograft rejection and their relevance for the induction of tolerance in the clinics.

Allergic asthma is a chronic inflammatory disease and despite the introduction of potent and effective drugs, the prevalence has increased substantially over the past few decades(1). The explanation that has attracted the most attention is the 'hygiene hypothesis', which suggests that the increase in allergic diseases is caused by a cleaner environment and fewer childhood infections(2-4). Indeed, certain mycobacterial strains can cause a shift from T-helper cell 2 (Th2) to Th1 immune responses, which may subsequently prevent the development of allergy in mice(5-7). Although the reconstitution of the balance between Th1 and Th2 is an attractive theory, it is unlikely to explain the whole story, as autoimmune diseases characterized by Th1 responses can also benefit from treatment with mycobacteria and their prevalence has also increased in parallel to allergies(8). Here we show that treatment of mice with SRP299, a killed Mycobacterium vaccae-suspension, gives rise to allergen-specific CD4(+)CD45RB(Lo) regulatory T cells, which confer protection against airway inflammation. This specific inhibition was mediated through interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta), as antibodies against IL-10 and TGF-beta completely reversed the inhibitory effect of CD4(+)CD45RB(Lo) T cells. Thus, regulatory T cells generated by mycobacteria treatment may have an essential role in restoring the balance of the immune system to prevent and treat allergic diseases.