Publications by authors named "Olivier Thaunat"

106 Publications

Characteristics of T and NK-cell Lymphomas After Renal Transplantation: a French National Multicentric Cohort Study.

Transplantation 2021 Feb 3. Epub 2021 Feb 3.

Department of Transplantation, Nephrology and Clinical Immunology, HCL Hôpital Edouard Herriot, and Université de Lyon, France Department of Hematology, HCL Centre Hospitalier Lyon Sud, and Université de Lyon, France CRCL, INSERM U1052, Pierre-Bénite, France CIRI, INSERM U1111, Lyon, France French PTLD Registry, University Hospital of Strasbourg, France Renal Transplantation Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital, Paris, France Department of Nephrology, AP-HM Hôpital de la Conception, Marseille, France Department of Nephrology and Transplantation, Hôpital Hôtel Dieu, Nantes, France Transplant Unit, Nephrology Department, University Hospital, Reims, France Transplant Unit, Department of Nephrology, University Hospital, Rennes, France Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France Department of Nephrology and Transplantation, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicetre, France Transplant Unit, Nephrology Department, University Hospital, Lille, France Transplant Unit, Nephrology Department, Besançon University Hospital, Besançon, France Transplant Unit, Nephrology Department, University Hospital, Amiens, France Nephrology Department, CHU Clermont-Ferrand, Clermont-Ferrand, France Department of Nephrology, Dupuytren Hospital, Limoges, France Department of Urology, Nephrology and Transplantation, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Henri-Mondor, Créteil, France Nephrology Department, CHU de Caen, Caen, France Transplant Unit, Nephrology Department, Dijon University Hospital, Dijon, France Department of Nephrology, University Hospital, Grenoble, France Department of Nephrology, Dialysis and Transplantation, Lapeyronie University Hospital, Montpellier, France Transplant Unit, Nephrology Department, Nancy University Hospital, Nancy, France epartment of Nephrology and Renal Transplantation, Hospital Pasteur, Nice, France Urgences Néphrologiques et Transplantation Rénale, Assistance Publique-Hôpitaux de Paris (AP-HP), Tenon Hospital, Paris, France Department of Nephrology and Transplantation, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint Louis Hospital, Paris, France Department of Nephrology Dialysis and Kidney Transplantation, CHU de Poitiers, Poitiers, France Nephrology, Dialysis and Renal Transplantation Department, Hôpital Nord, CHU de Saint-Etienne, France Nephrology, Dialysis and Renal Transplantation Department, Centre Hospitalier Régional Universitaire Tours, France INSERM U955, Université Paris-Est, and Department of pathology, APHP Hôpital Henri Mondor, Créteil, France Department of Hematology, APHP Hôpital Pitié-Salpétrière, Paris, France. Etablissement Français du Sang, Lyon, France Department of Nephrology and Transplantation, University Hospital of Strasbourg, France.

Background: Posttransplant Lymphoproliferative Disorders (PTLD) encompass a spectrum of heterogeneous entities. Because the vast majority of cases PTLD arise from B cells, available data on PTLD of T or NK phenotype (T/NK-cell PTLD) are scarce, which limits the quality of the management of these patients.

Methods: All adult cases of PTLD diagnosed in France were prospectively recorded in the national registry between 1998 and 2007. Crosschecking the registry data with 2 other independent national databases identified 58 cases of T/NK-cell PTLD. This cohort was then compared with: i) the 395 cases of B-cell PTLD from the registry, and of ii) a cohort of 148 T/NK-cell lymphomas diagnosed in nontransplanted patients.

Results: T/NK-cell PTLD occurred significantly later after transplantation and had a worse overall survival than B-cell PTLD. Two subtypes of T/NK-cell PTLD were distinguished: i) cutaneous (28%) and ii) systemic (72%), the latter being associated with a worse prognosis. Compared with T/NK-cell lymphomas of nontransplanted patients, overall survival of systemic T/NK-cell PTLD was worse (HR: 2.64[1.76-3.94]; p<0.00001).

Conclusions: This difference, which persisted after adjustment on tumoral mass, histological subtype, and extension of the disease at diagnosis could be explained by the fact that transplanted patients were less intensively treated and responded less to chemotherapy.
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http://dx.doi.org/10.1097/TP.0000000000003568DOI Listing
February 2021

Impact of Covid-19 on kidney transplant and waiting list patients: Lessons from the first wave of the pandemic.

Nephrol Ther 2021 Jan 8. Epub 2021 Jan 8.

Department of Nephrology and Transplantation, Lille University Hospital, Lille, France.

Background: The first wave of the Covid-19 pandemic resulted in a drastic reduction in kidney transplantation and a profound change in transplant care in France. It is critical for kidney transplant centers to understand the behaviors, concerns and wishes of transplant recipients and waiting list candidates.

Methods: French kidney patients were contacted to answer an online electronic survey at the end of the lockdown.

Results: At the end of the first wave of the pandemic in France (11 May 2020), 2112 kidney transplant recipients and 487 candidates answered the survey. More candidates than recipients left their home during the lockdown, mainly for health care (80.1% vs. 69.4%; P<0.001). More candidates than recipients reported being exposed to Covid-19 patients (2.7% vs. 1.2%; P=0.006). Many recipients and even more candidates felt inadequately informed by their transplant center during the pandemic (19.6% vs. 54%; P<0.001). Among candidates, 71.1% preferred to undergo transplant as soon as possible, 19.5% preferred to wait until Covid-19 had left their community, and 9.4% were not sure what to do.

Conclusions: During the Covid-19 pandemic in France, the majority of candidates wished to receive a transplant as soon as possible without waiting until Covid-19 had left their community. Communication between kidney transplant centers and patients must be improved to better understand and serve patients' needs.
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http://dx.doi.org/10.1016/j.nephro.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791308PMC
January 2021

The authors reply.

Kidney Int 2021 03 11;99(3):771-772. Epub 2021 Jan 11.

Department of Nephrology and Transplantation, Strasbourg University Hospital, Strasbourg, France.

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http://dx.doi.org/10.1016/j.kint.2020.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797773PMC
March 2021

Revisiting the changes in the Banff classification for antibody-mediated rejection after kidney transplantation.

Am J Transplant 2020 Dec 31. Epub 2020 Dec 31.

Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.

The Banff classification for antibody-mediated rejection (ABMR) has undergone important changes, mainly by inclusion of C4d-negative ABMR in Banff'13 and elimination of suspicious ABMR (sABMR) with the use of C4d as surrogate for HLA-DSA in Banff'17. We aimed to evaluate the numerical and prognostic repercussions of these changes in a single-center cohort study of 949 single kidney transplantations, comprising 3662 biopsies that were classified according to the different versions of the Banff classification. Overall, the number of ABMR and sABMR cases increased from Banff'01 to Banff'13. In Banff'17, 248 of 292 sABMR biopsies were reclassified to No ABMR, and 44 of 292 to ABMR. However, reclassified sABMR biopsies had worse and better outcome than No ABMR and ABMR, which was mainly driven by the presence of microvascular inflammation and absence of HLA-DSA, respectively. Consequently, the discriminative performance for allograft failure was lowest in Banff'17, and highest in Banff'13. Our data suggest that the clinical and histological heterogeneity of ABMR is inadequately represented in a binary classification system. This study provides a framework to evaluate the updates of the Banff classification and assess the impact of proposed changes on the number of cases and risk stratification. Two alternative classifications introducing an intermediate category are explored.
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http://dx.doi.org/10.1111/ajt.16474DOI Listing
December 2020

Combined Liver-Kidney Transplantation With Preformed Anti-human Leukocyte Antigen Donor-Specific Antibodies.

Kidney Int Rep 2020 Dec 3;5(12):2202-2211. Epub 2020 Oct 3.

Department of Nephrology and Organ Transplantation, Toulouse University Hospital (Centre Hospitalier et Universitaire), Toulouse, France.

Introduction: The impact of preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (pDSAs) after combined liver-kidney transplantation (CLKT) is still uncertain.

Methods: We conducted a retrospective study in 8 European high-volume transplant centers and investigated the outcome of 166 consecutive CLKTs, including 46 patients with pDSAs.

Results: Patient survival was lower in those with pDSAs (5-year patient survival rate of 63% and 78% with or without pDSA, respectively;  = 0.04). The presence of pDSAs with a mean fluorescence intensity (MFI) ≥ 5000 (hazard ratio 4.96; 95% confidence interval: 2.3-10.9;  < 0.001) and the presence of 3 or more pDSAs (hazard ratio 6.5; 95% confidence interval: 2.5-18.8;  = 0.05) were independently associated with death. The death-censored liver graft survival was similar in patients with or without pDSAs. Kidney graft survival was comparable in both groups. (The 1- and 5-year death-censored graft survival rates were 91.6% and 79.5%, respectively, in patients with pDSAs and 93% and 88%, respectively, in the donor-specific antibody [DSA]-negative group,  = not significant). Despite a higher rate of kidney graft rejection in patients with pDSAs (5-year kidney graft survival rate without rejection of 87% and 97% with or without pDSAs, respectively;  = 0.04), kidney function did not statistically differ between both groups at 5 years post-transplantation (estimated glomerular filtration rate 45 ± 17 vs. 57 ± 29 ml/min per 1.73 m, respectively, in patients with and without pDSAs). Five recipients with pDSAs (11.0%) experienced an antibody-mediated kidney rejection that led to graft loss in 1 patient.

Conclusion: Our results suggest that CLKT with pDSAs is associated with a lower patients' survival despite good recipients', liver and kidney grafts' outcome.
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http://dx.doi.org/10.1016/j.ekir.2020.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710847PMC
December 2020

Is COVID-19 infection more severe in kidney transplant recipients?

Am J Transplant 2021 03 28;21(3):1295-1303. Epub 2021 Jan 28.

Department of Infectious Diseases, Strasbourg University Hospital, Strasbourg, France.

There are no studies which have compared the risk of severe COVID-19 and related mortality between transplant recipients and nontransplant patients. We enrolled two groups of patients hospitalized for COVID-19, that is, kidney transplant recipients (KTR) from the French Registry of Solid Organ Transplant (n = 306) and a single-center cohort of nontransplant patients (n = 795). An analysis was performed among subgroups matched for age and risk factors for severe COVID-19 or mortality. Severe COVID-19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death. Transplant recipients were younger and had more comorbidities compared to nontransplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30-day cumulative incidence of severe COVID-19 did not differ between KTR and nontransplant patients; however, 30-day COVID-19-related mortality was significantly higher in KTR (17.9% vs 11.4%, respectively, p = .038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein (CRP) were associated with severe COVID-19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR = 1.55), and creatinine level >115 µmol/L (HR = 2.32) were associated with COVID-19-related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. KTR had a higher COVID-19-related mortality compared to nontransplant hospitalized patients.
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http://dx.doi.org/10.1111/ajt.16424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753418PMC
March 2021

Missing Self-Induced Activation of NK Cells Combines with Non-Complement-Fixing Donor-Specific Antibodies to Accelerate Kidney Transplant Loss in Chronic Antibody-Mediated Rejection.

J Am Soc Nephrol 2021 Feb 25;32(2):479-494. Epub 2020 Nov 25.

International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France

Background: Binding of donor-specific antibodies (DSAs) to kidney allograft endothelial cells that does not activate the classic complement cascade can trigger the recruitment of innate immune effectors, including NK cells. Activated NK cells contribute to microvascular inflammation leading to chronic antibody-mediated rejection (AMR). Recipient NK cells can also trigger antibody-independent microvascular inflammation by sensing the absence of self HLA class I molecules ("missing self") on allograft endothelial cells. This translational study investigated whether the condition of missing self amplifies DSA-dependent NK cell activation to worsen chronic AMR.

Methods And Results: Among 1682 kidney transplant recipients who underwent an allograft biopsy at Lyon University Hospital between 2004 and 2017, 135 fulfilled the diagnostic criteria for AMR and were enrolled in the study. Patients with complement-fixing DSAs identified by a positive C3d binding assay (=73, 54%) had a higher risk of transplant failure (=0.002). Among the remaining patients with complement-independent chronic AMR (=62, 46%), those in whom missing self was identified through donor and recipient genotyping exhibited worse allograft survival (=0.02). In multivariable analysis, only proteinuria (HR: 7.24; =0.01) and the presence of missing self (HR: 3.57; =0.04) were independent predictors for transplant failure following diagnosis of chronic AMR. Cocultures of human NK cells and endothelial cells confirmed that addition of missing self to DSA-induced NK cell activation increased endothelial damage.

Conclusions: The assessment of missing self at the time of diagnosis of chronic AMR identifies patients at higher risk for kidney transplant failure.
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http://dx.doi.org/10.1681/ASN.2020040433DOI Listing
February 2021

[Missing self-induced NK cell activation promotes "innate" chronic vascular rejection of transplanted organs].

Med Sci (Paris) 2020 Nov 5;36(11):984-987. Epub 2020 Nov 5.

CIRI, Inserm U1111, Université Claude Bernard Lyon I, CNRS UMR5308, École normale supérieure de Lyon, Univ. Lyon, 21 avenue Tony-Garnier, 69007 Lyon, France. - Hospices civils de Lyon, Hôpital Edouard Herriot, Service de transplantation, néphrologie et immunologie clinique, 5 place d'Arsonval, 69003 Lyon, France. - Faculté de médecine Lyon-Est, Université Claude Bernard Lyon I, 8 avenue Rockfeller, 69373 Lyon, France.

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http://dx.doi.org/10.1051/medsci/2020183DOI Listing
November 2020

IMPact of the COVID-19 epidemic on the moRTAlity of kidney transplant recipients and candidates in a French Nationwide registry sTudy (IMPORTANT).

Kidney Int 2020 12 31;98(6):1568-1577. Epub 2020 Oct 31.

Department of Nephrology and Transplantation, Strasbourg University Hospital, Strasbourg, France.

End stage kidney disease increase the risk of COVID-19 related death but how the kidney replacement strategy should be adapted during the pandemic is unknown. Chronic hemodialysis makes social distancing difficult to achieve. Alternatively, kidney transplantation could increase the severity of COVID-19 due to therapeutic immunosuppression and contribute to saturation of intensive care units. For these reasons, kidney transplantation was suspended in France during the first epidemic wave. Here, we retrospectively evaluated this strategy by comparing the overall and COVID-19 related mortality in kidney transplant recipients and candidates over the last three years. Cross-interrogation of two national registries for the period 1 March and 1 June 2020, identified 275 deaths among the 42812 kidney transplant recipients and 144 deaths among the 16210 candidates. This represents an excess of deaths for both populations, as compared with the same period the two previous years (mean of two previous years: 253 in recipients and 112 in candidates). This difference was integrally explained by COVID-19, which accounted for 44% (122) and 42% (60) of the deaths in recipients and candidates, respectively. Taking into account the size of the two populations and the geographical heterogeneity of virus circulation, we found that the excess of risk of death due to COVID-19 was similar for recipients and candidates in high viral risk area but four-fold higher for candidates in the low viral risk area. Thus, in case of a second epidemic wave, kidney transplantation should be suspended in high viral risk areas but maintained outside those areas, both to reduce the excess of deaths of candidates and avoid wasting precious resources.
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http://dx.doi.org/10.1016/j.kint.2020.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604114PMC
December 2020

An initial report from the French SOT COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants.

Kidney Int 2020 12 24;98(6):1549-1558. Epub 2020 Aug 24.

Department of Nephrology and Transplantation, University of Lille, Lille, France.

Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in recipients of a kidney transplant remain scanty. The aim of this registry-based observational study was to explore characteristics and clinical outcomes of recipients of kidney transplants included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. Covid-19 was diagnosed in symptomatic patients who had a positive PCR assay for SARS-CoV-2 or having typical lung lesions on imaging. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. Risk factors for severe disease or death were determined. Of the 279 patients, 243 were admitted to hospital and 36 were managed at home. The median age of hospitalized patients was 61.6 years; most had comorbidities (hypertension, 90.1%; overweight, 63.8%; diabetes, 41.3%; cardiovascular disease, 36.2%). Fever, cough, dyspnea, and diarrhea were the most common symptoms on admission. Laboratory findings revealed mild inflammation frequently accompanied by lymphopenia. Immunosuppressive drugs were generally withdrawn (calcineurin inhibitors: 28.7%; antimetabolites: 70.8%). Treatment was mainly based on hydroxychloroquine (24.7%), antiviral drugs (7.8%), and tocilizumab (5.3%). Severe Covid-19 occurred in 106 patients (46%). Forty-three hospitalized patients died (30-day mortality 22.8%). Multivariable analysis identified overweight, fever, and dyspnea as independent risk factors for severe disease, whereas age over 60 years, cardiovascular disease, and dyspnea were independently associated with mortality. Thus, Covid-19 in recipients of kidney transplants portends a high mortality rate. Proper management of immunosuppression and tailored treatment of this population remain challenging.
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http://dx.doi.org/10.1016/j.kint.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444636PMC
December 2020

Transcriptional Changes in Kidney Allografts with Histology of Antibody-Mediated Rejection without Anti-HLA Donor-Specific Antibodies.

J Am Soc Nephrol 2020 09 8;31(9):2168-2183. Epub 2020 Jul 8.

Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium

Background: Circulating donor-specific anti-HLA antibodies (HLA-DSAs) are often absent in serum of kidney allograft recipients whose biopsy specimens demonstrate histology of antibody-mediated rejection (ABMR). It is unclear whether cases involving ABMR histology without detectable HLA-DSAs represent a distinct clinical and molecular phenotype.

Methods: In this multicenter cohort study, we integrated allograft microarray analysis with extensive clinical and histologic phenotyping from 224 kidney transplant recipients between 2011 and 2017. We used the term ABMR histology for biopsy specimens that fulfill the first two Banff 2017 criteria for ABMR, irrespective of HLA-DSA status.

Results: Of 224 biopsy specimens, 56 had ABMR histology; 26 of these (46.4%) lacked detectable serum HLA-DSAs. Biopsy specimens with ABMR histology showed overexpression of transcripts mostly related to IFN-induced pathways and activation of natural killer cells and endothelial cells. HLA-DSA-positive and HLA-DSA-negative biopsy specimens with ABMR histology displayed similar upregulation of pathways and enrichment of infiltrating leukocytes. Transcriptional heterogeneity observed in biopsy specimens with ABMR histology was not associated with HLA-DSA status but was caused by concomitant T cell-mediated rejection. Compared with cases lacking ABMR histology, those with ABMR histology and HLA-DSA had higher allograft failure risk (hazard ratio [HR], 7.24; 95% confidence interval [95% CI], 3.04 to 17.20) than cases without HLA-DSA (HR, 2.33; 95% CI, 0.85 to 6.33), despite the absence of transcriptional differences.

Conclusions: ABMR histology corresponds to a robust intragraft transcriptional signature, irrespective of HLA-DSA status. Outcome after ABMR histology is not solely determined by the histomolecular presentation but is predicted by the underlying etiologic factor. It is important to consider this heterogeneity in further research and in treatment decisions for patients with ABMR histology.
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http://dx.doi.org/10.1681/ASN.2020030306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461663PMC
September 2020

Diagnostic performance of kSORT, a blood-based mRNA assay for noninvasive detection of rejection after kidney transplantation: A retrospective multicenter cohort study.

Am J Transplant 2021 02 4;21(2):740-750. Epub 2020 Aug 4.

French National Institute of Health and Medical Research (Inserm) Unit 1111, Lyon, France.

The Kidney Solid Organ Response Test (kSORT) blood gene expression assay was developed to noninvasively detect acute rejection (AR) after kidney transplantation. Its performance in a setting with natural disease prevalence has not been evaluated. A retrospective, multicenter cohort study was conducted across all single kidney transplant recipients, transplanted between 2011 and 2015, with samples within the first year after transplantation available in existing biobanks. The primary objective was to determine the diagnostic performance of the kSORT assay to detect AR (T cell-mediated and/or antibody-mediated rejection) as compared to a concomitant renal biopsy. AR was reported on the concomitant biopsy in 188 of 1763 (10.7%) blood samples and any rejection (including borderline changes) in 614 of 1763 (34.8%) blood samples. In 320 of 1763 samples (18.2%) the kSORT risk category was indeterminate. The kSORT assay had no diagnostic value for AR (area under the curve [AUC] 0.51, 95% confidence interval [CI] 0.50-0.56; P = .46) overall, or when considering indication biopsies (N = 487) and protocol-specified biopsies (N = 1276) separately (AUC of 0.53, 95% CI 0.50-0.59, P = .44 and 0.55, 95% CI 0.50-0.61, P = .09, respectively). This large retrospective study utilizing samples obtained under real-world clinical conditions, was unable to validate the kSORT assay for detection of AR in the first year after transplantation.
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http://dx.doi.org/10.1111/ajt.16179DOI Listing
February 2021

Chronic Kidney Disease-Associated Immune Dysfunctions: Impact of Protein-Bound Uremic Retention Solutes on Immune Cells.

Toxins (Basel) 2020 05 6;12(5). Epub 2020 May 6.

Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, Hospices Civils de Lyon, 69000 Lyon, France.

Regardless of the primary disease responsible for kidney failure, patients suffering from chronic kidney disease (CKD) have in common multiple impairments of both the innate and adaptive immune systems, the pathophysiology of which has long remained enigmatic. CKD-associated immune dysfunction includes chronic low-grade activation of monocytes and neutrophils, which induces endothelial damage and increases cardiovascular risk. Although innate immune effectors are activated during CKD, their anti-bacterial capacity is impaired, leading to increased susceptibility to extracellular bacterial infections. Finally, CKD patients are also characterized by profound alterations of cellular and humoral adaptive immune responses, which account for an increased risk for malignancies and viral infections. This review summarizes the recent emerging data that link the pathophysiology of CKD-associated immune dysfunctions with the accumulation of microbiota-derived metabolites, including indoxyl sulfate and p-cresyl sulfate, the two best characterized protein-bound uremic retention solutes.
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http://dx.doi.org/10.3390/toxins12050300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291164PMC
May 2020

Comparison of creatinine-based equations for estimating glomerular filtration rate in deceased donor renal transplant recipients.

PLoS One 2020 28;15(4):e0231873. Epub 2020 Apr 28.

Néphrologie, Dialyse, Hypertension et Exploration Fonctionnelle Rénale, Groupement Hospitalier Edouard Herriot, Hospices Civils de Lyon, Lyon, France.

Background: Estimating glomerular filtration rate (GFR) is important for clinical management in kidney transplantation recipients (KTR). However, very few studies have evaluated the performance of the new GFR estimating equations (Lund-Malmö Revised-LMR, and Full Age Spectrum-FAS) in KTR.

Methods: GFR was estimated (eGFR) using CKD-EPI, MDRD, LMR, and FAS equations and compared to GFR measurement (mGFR) by reference methods (inuline urinary and iohexol plasma clearance) in 395 deceased-donor KTR without corticosteroids. The equations performance was assessed using bias (mean difference of eGFR and mGFR), precision (standard deviation of the difference), accuracy (concordance correlation coefficient-CCC), and agreements (total deviation index-TDI). The area under receiver operating characteristic curves (ROC) and the likelihood ratio for a positive result were calculated.

Results: In the total population, the performance of the CKD-EPI, MDRD and FAS equations was significantly lower than the LMR equation regarding the mean [95%CI] difference in bias (-2.0 [-4.0; -1.5] versus 9.0 [7.5; 10.0], 5.0 [3.5; 6.0] and 10.0 [8.5; 11.0] mL/min/1.73m2, P<0.005) and TDI (17.10 [16.41; 17.88], 25.91 [24.66; 27.16], 21.23 [19.48; 23.13] and 25.84 [24.16; 27.57], respectively). Concerning the CCC, all equation had poor agreement (<0.800) without statically difference between them. However, all equations had excellent area under the ROC curve (>0.900), and LMR equation had the best ability to correctly predict KTR with mGFR<45 mL/min/1.73 m2 (positive likelihood ratio: 8.87 [5.79; 13.52]).

Conclusion: Among a referral group of subjects KTR, LMR equation had the best mean bias and TDI, but with no significant superiority in other agreement tools. Caveat is required in the use and interpretation of PCr-based equations in this specific population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231873PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188287PMC
July 2020

Humoral Alloreactivity in VCA Recipients: Should We Learn From Our Experience?

Transplantation 2020 10;104(10):2003-2010

Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot University Hospital, Lyon, France.

Initially overlooked in favor of T cell-mediated rejection, the importance of the humoral alloimmune response has progressively emerged. As a result, antibody-mediated rejection is now widely recognized as the main cause of late allograft loss in most (if not all) types of solid-organ transplantation. Over the last 2 decades, vascularized composite allotransplantation (VCA) has appeared for replacing tissue defects in patients for whom no other satisfactory reconstructive options were available. Although it is now clear that VCA recipients can develop donor-specific antibodies, conclusions made in solid organ transplantation regarding antibody-mediated rejection may not systematically apply to VCA. Here, we propose to use the experience gained in organ transplantation to shed light on the path that shall be followed to evaluate and manage humoral alloreactivity in VCA recipients.
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http://dx.doi.org/10.1097/TP.0000000000003164DOI Listing
October 2020

[Immunological aspects of vascularised composite tissue grafts].

Soins 2019 Oct;64(839):20-21

Université de Lyon, 92, rue Pasteur, CS 30122, 69361 Lyon Cedex 07, France; Service d'urologie et de transplantation, Hôpital Édouard-Herriot, Hospices civils de Lyon, 5, place d'Arsonval, 69003 Lyon, France.

The progress of immuno-suppressive treatments in recent years has largely conditioned advances and successes in allotransplantations of vascularised composite tissues, especially the hands and face. However, rejection phenomena are not fully controlled, as in other organ transplants.
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http://dx.doi.org/10.1016/j.soin.2019.09.006DOI Listing
October 2019

Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants.

Nat Commun 2019 11 25;10(1):5350. Epub 2019 Nov 25.

CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France.

Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.
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http://dx.doi.org/10.1038/s41467-019-13113-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877588PMC
November 2019

Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study.

BMJ 2019 09 17;366:l4923. Epub 2019 Sep 17.

Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, Paris, France.

Objective: To develop and validate an integrative system to predict long term kidney allograft failure.

Design: International cohort study.

Setting: Three cohorts including kidney transplant recipients from 10 academic medical centres from Europe and the United States.

Participants: Derivation cohort: 4000 consecutive kidney recipients prospectively recruited in four French centres between 2005 and 2014. Validation cohorts: 2129 kidney recipients from three centres in Europe and 1428 from three centres in North America, recruited between 2002 and 2014. Additional validation in three randomised controlled trials (NCT01079143, EudraCT 2007-003213-13, and NCT01873157).

Main Outcome Measure: Allograft failure (return to dialysis or pre-emptive retransplantation). 32 candidate prognostic factors for kidney allograft survival were assessed.

Results: Among the 7557 kidney transplant recipients included, 1067 (14.1%) allografts failed after a median post-transplant follow-up time of 7.12 (interquartile range 3.51-8.77) years. In the derivation cohort, eight functional, histological, and immunological prognostic factors were independently associated with allograft failure and were then combined into a risk prediction score (iBox). This score showed accurate calibration and discrimination (C index 0.81, 95% confidence interval 0.79 to 0.83). The performance of the iBox was also confirmed in the validation cohorts from Europe (C index 0.81, 0.78 to 0.84) and the US (0.80, 0.76 to 0.84). The iBox system showed accuracy when assessed at different times of evaluation post-transplant, was validated in different clinical scenarios including type of immunosuppressive regimen used and response to rejection therapy, and outperformed previous risk prediction scores as well as a risk score based solely on functional parameters including estimated glomerular filtration rate and proteinuria. Finally, the accuracy of the iBox risk score in predicting long term allograft loss was confirmed in the three randomised controlled trials.

Conclusion: An integrative, accurate, and readily implementable risk prediction score for kidney allograft failure has been developed, which shows generalisability across centres worldwide and common clinical scenarios. The iBox risk prediction score may help to guide monitoring of patients and further improve the design and development of a valid and early surrogate endpoint for clinical trials.

Trial Registration: Clinicaltrials.gov NCT03474003.
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http://dx.doi.org/10.1136/bmj.l4923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746192PMC
September 2019

Highly Variable Sialylation Status of Donor-Specific Antibodies Does Not Impact Humoral Rejection Outcomes.

Front Immunol 2019 20;10:513. Epub 2019 Mar 20.

French National Institute of Health and Medical Research (INSERM) Unit 1111, Lyon, France.

Clinical outcome in antibody-mediated rejection (AMR) shows high inter-individual heterogeneity. Sialylation status of the Fc fragment of IgGs is variable, which could modulate their ability to bind to C1q and/or Fc receptors. In this translational study, we evaluated whether DSA sialylation influence AMR outcomes. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of DSA by Luminex. The sialylation status of total IgG and DSA was quantified using agglutinin-based chromatography. All patients had similar levels of sialylation of serum IgGs (~2%). In contrast, the proportion of sialylated DSA were highly variable (median = 9%; range = 0-100%), allowing to distribute the patients in two groups: high DSA sialylation ( = 44; 64%) and low DSA sialylation ( = 25; 36%). The two groups differed neither on the intensity of rejection lesions (C4d, ptc, and g; > 0.05) nor on graft survival rates (Log rank test, = 0.99). odels confirmed the lack of impact of Fc sialylation on the ability of a monoclonal antibody to trigger classical complement cascade and activate NK cells. We conclude that DSA sialylation status is highly variable but has not impact on DSA pathogenicity and AMR outcome.
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http://dx.doi.org/10.3389/fimmu.2019.00513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435580PMC
September 2020

Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens.

J Am Soc Nephrol 2019 04 8;30(4):692-709. Epub 2019 Mar 8.

Paris Descartes, Sorbonne Paris Cité University, Paris, France;

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 cell-based assays are needed to improve risk assessments before transplant.
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http://dx.doi.org/10.1681/ASN.2018080868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442343PMC
April 2019

Residual Activatability of Circulating Tfh17 Predicts Humoral Response to Thymodependent Antigens in Patients on Therapeutic Immunosuppression.

Front Immunol 2018 5;9:3178. Epub 2019 Feb 5.

French National Institute of Health and Medical Research (Inserm) Unit 1111, Lyon, France.

The generation of antibodies against protein antigens (such as donor-specific HLA molecules) requires that T follicular helper cells (Tfh) provide help to B cells. Immunosuppressive (IS) armamentarium prevents T cell activation, yet a significant proportion of renal transplant patients develop donor-specific antibodies (DSA), which suggests that IS drugs do not efficiently block T follicular helper cells. To test this hypothesis, the number of circulating Tfh, their polarization profile, and ability to up-regulate (i) the co-stimulatory molecules CD40L and ICOS, and (ii) the activation marker CD25, following stimulation in presence of IS drugs, were compared between 36 renal transplant patients (6-72 months post transplantation) and nine healthy controls. IS drugs reduced the number of Tfh1 and 2 but had little impact on Tfh17, which was the dominant subset in transplant patients. Although, IS drugs decreased activation-induced expression of co-stimulatory molecules by Tfh, the impact was highly variable between individuals. Furthermore, 20% of transplant patients displayed normal expression of CD25 on Tfh following stimulation (i.e., "residual activatability"). To test whether residual activatability of Tfh correlates with antibody response against thymo-dependent antigens we took advantage of the 2015 influenza vaccination campaign, which provided a normalized setting for antigenic stimulation. In line with our hypothesis, responders to influenza vaccine exhibited significantly higher percentage of CD25-expressing Tfh17 after stimulation. A results that was confirmed retrospectively in nine transplanted patients at the time of first DSA detection. We concluded that "residual activatability" of Tfh17 might be used as a non-invasive biomarker to identify transplant patients at higher risk to develop DSA under immunosuppression. If validated in larger studies, this assay might help optimizing the prevention of DSA through personalized adaptation of immunosuppressive regimen.
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http://dx.doi.org/10.3389/fimmu.2018.03178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370621PMC
October 2019

Pregnancy and donor-specific HLA-antibody-mediated rejection after liver transplantation: "Liaisons dangereuses"?

Transpl Immunol 2019 06 8;54:47-51. Epub 2019 Feb 8.

Etablissement Français du Sang, Lyon, France.

Background: Risk factors for the development of anti-HLA antibodies include blood transfusion, organ transplantation, and pregnancy. Humoral rejection, mediated by donor-specific anti-HLA antibodies (DSA), has been studied in all kind of solid organ transplantations, and several studies have suggested that post-liver transplantation (LT) DSA may play a role in acute and chronic rejection.

Objective: The aim of the present study was to assess the impact of pregnancy on the occurrence of DSA and the impact of DSA in a large population of young female LT recipients.

Methods: This single center retrospective study included all female patients who underwent a first LT between January 1990 and December 2010 and who were of childbearing age during post-LT follow-up (i.e. 18 to 40 years old).

Results: The study population consisted in 73 patients, and the mean age at LT was 20.9 years (0.6-39.9); 32 patients were transplanted during childhood. The global incidence of de novo DSA was 42.5% (31/73), after a median delay of 15.5 years (1-25) of follow-up after LT. Most de novo DSA were anti-class II alone (90.3%), and included anti-DQ for 80.6%. From the 73 patients, 33 presented at least one pregnancy after LT (45.2%) and before DSA screening. Multivariate analysis disclosed that history of pregnancy (OR = 6.37; 95%CI, 2.17-18.63, p = 0.001) and younger age at LT (OR = 0.96; 95%CI:0.92-0.99, p = 0.033) were significantly associated with de novo DSA. Among the 31 patients who had de novo DSA, the diagnosis of antibody-mediated rejection was made in 8 patients (25.8%), after a median delay of 74 months after LT; 6/8 (75.0%) had history of pregnancy. During follow-up, 3 of these 8 patients lost their liver graft and died.

Conclusion: The results of the present study suggest that close monitoring of DSA in young women with history of pregnancy should be recommended regarding the risk of DSA-mediated rejection.
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http://dx.doi.org/10.1016/j.trim.2019.02.002DOI Listing
June 2019

Infections after upper extremity allotransplantation: a worldwide population cohort study, 1998-2017.

Transpl Int 2019 Jul 29;32(7):693-701. Epub 2019 Jan 29.

Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.

Risk-to-benefit analysis of upper extremity allotransplantation (UEA) warrants a careful assessment of immunosuppression-related complications. This first systematic report of infectious complications after UEA aimed to compare incidence and pattern of infections to that observed after kidney transplantation (KT). We conducted a matched cohort study among UEA and KT recipients from the International Registry on Hand and Composite Tissue Transplantation and the French transplant database DIVAT. All UEA recipients between 1998 and 2016 were matched with KT recipients (1:5) regarding age, sex, cytomegalovirus (CMV) serostatus and induction treatment. Infections were analyzed at three posttransplant periods (early: 0-6 months, intermediate: 7-12 months, late: >12 months). Sixty-one UEA recipients and 305 KT recipients were included. Incidence of infection was higher after UEA than after KT during the early period (3.27 vs. 1.95 per 1000 transplant-days, P = 0.01), but not statistically different during the intermediate (0.61 vs. 0.45/1000, P = 0.5) nor the late period (0.15 vs. 0.21/1000, P = 0.11). The distribution of infectious syndromes was significantly different, with mucocutaneous infections predominating after UEA, urinary tract infections and pneumonia predominating after KT. Incidence of infection is high during the first 6 months after UEA. After 1 year, the burden of infections is low, with favorable patterns.
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http://dx.doi.org/10.1111/tri.13399DOI Listing
July 2019

Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation.

Kidney Int 2019 01 3;95(1):188-198. Epub 2018 Nov 3.

Laboratory of Nephrology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Despite partial elucidation of the pathophysiology of antibody-mediated rejection (ABMR) after kidney transplantation, it remains largely unclear which of the involved immune cell types determine disease activity and outcome. We used microarray transcriptomic data from a case-control study (n=95) to identify genes that are differentially expressed in ABMR. Given the co-occurrence of ABMR and T-cell-mediated rejection (TCMR), we built a bioinformatics pipeline to distinguish ABMR-specific mRNA markers. Differential expression of 503 unique genes was identified in ABMR, with significant enrichment of natural killer (NK) cell pathways. CIBERSORT (Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts) deconvolution analysis was performed to elucidate the corresponding cell subtypes and showed increased NK cell infiltration in ABMR in comparison to TCMR and normal biopsies. Other leukocyte types (including monocytes/macrophages, CD4 and CD8 T cells, and dendritic cells) were increased in rejection, but could not discriminate ABMR from TCMR. Deconvolution-based estimation of NK cell infiltration was validated using computerized morphometry, and specifically associated with glomerulitis and peritubular capillaritis. In an external data set of kidney transplant biopsies, activated NK cell infiltration best predicted graft failure amongst all immune cell subtypes and even outperformed a histologic diagnosis of acute rejection. These data suggest that NK cells play a central role in the pathophysiology of ABMR and graft failure after kidney transplantation.
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http://dx.doi.org/10.1016/j.kint.2018.08.027DOI Listing
January 2019

Performances of creatinine-based glomerular filtration rate estimating equations in simultaneous pancreas-kidney transplant recipients: a single center cohort study.

Transpl Int 2019 01 19;32(1):75-83. Epub 2018 Sep 19.

Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, Lyon, France.

Estimating glomerular filtration rate (GFR) is important for clinical management and research studies in simultaneous pancreas-kidney transplantation (SPK) recipients. No study has specifically investigated the reliability of recent creatinine-based GFR estimating equations in this singular population. We assessed the performances of CKD-EPI, MDRD, Schwartz-2009, Schwartz-Lyon, Lund-Malmo and Full Age Spectrum equations for estimating GFR after SPK. 126 patients were included. GFR was measured by a reference method (mGFR) one year after SPK and estimated with the different equations from a standardized measure of serum creatinine. Relative bias, precisions, 10% and 30% accuracies (P30) were used to determine equations reliability. Ages ranged from 29 to 58. Mean mGFR was 56.3 ± 13.3 [23.6-92.5] ml/min/1.73 m . In the whole population, P30 of the CKD-EPI and MDRD equations were 42% (38.0; 46.0) and 65% (61.5; 69) respectively. As compared to the other equations, the Schwartz-Lyon equation was significantly more accurate (P30 = 86.0% [83.5-88.0], P < 0.01) and less biased (1.13 [1.06-1.19], P < 0.01). Conclusions were similar whatever the age class (<40 or ≥40) and mGFR level (<60 or ≥60 ml/min/1.73 m ). This study suggests that the CKD-EPI and MDRD equations have poor performances in SPK recipients and that the Schwartz-Lyon equation is a reliable alternative.
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http://dx.doi.org/10.1111/tri.13333DOI Listing
January 2019

SYK Inhibition Induces Apoptosis in Germinal Center-Like B Cells by Modulating the Antiapoptotic Protein Myeloid Cell Leukemia-1, Affecting B-Cell Activation and Antibody Production.

Front Immunol 2018 24;9:787. Epub 2018 Apr 24.

Institut Francilien de Recherche en Nephrologie et Transplantation (IFRNT), Service de Néphrologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France.

B cells play a major role in the antibody-mediated rejection (AMR) of solid organ transplants, a major public health concern. The germinal center (GC) is involved in the generation of donor-specific antibody-producing plasma cells and memory B cells, which are often poorly controlled by current treatments. Myeloid cell leukemia-1 (Mcl-1), an antiapoptotic member of the B-cell lymphoma-2 family, is essential for maintenance of the GC reaction and B-cell differentiation. During chronic AMR (cAMR), tertiary lymphoid structures resembling GCs appear in the rejected organ, suggesting local lymphoid neogenesis. We report the infiltration of the kidneys with B cells expressing Mcl-1 in patients with cAMR. We modulated GC viability by impairing B-cell receptor signaling, by spleen tyrosine kinase (SYK) inhibition. SYK inhibition lowers viability and Mcl-1 protein levels in Burkitt's lymphoma cell lines. This downregulation of Mcl-1 is coordinated at the transcriptional level, possibly by signal transducer and activator of transcription 3 (STAT3), as shown by (1) the impaired translocation of STAT3 to the nucleus following SYK inhibition, and (2) the lower levels of Mcl-1 transcription upon STAT3 inhibition. Mcl-1 overproduction prevented cells from entering apoptosis following SYK inhibition. studies with primary tonsillar B cells confirmed that SYK inhibition impaired cell survival and decreased Mcl-1 protein levels. It also impaired B-cell activation and immunoglobulin G secretion by tonsillar B cells. These findings suggest that the SYK-Mcl-1 pathway could be targeted, to improve graft survival by manipulating the humoral immune response.
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http://dx.doi.org/10.3389/fimmu.2018.00787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928208PMC
June 2019

The disappointing contribution of anti-human leukocyte antigen donor-specific antibodies characteristics for predicting allograft loss.

Nephrol Dial Transplant 2018 10;33(10):1853-1863

Centre Hospitalier Universitaire de Bordeaux, Laboratoire d'Immunologie et Immunogénétique, Hôpital Pellegrin, Bordeaux, France.

Background: Pathogenicity of donor-specific antibodies (DSAs) can be assessed using the single-antigen flow beads (SAFB) assays through mean fluorescence intensity (MFI) with or without serum ethylenediaminetetraacetic acid (EDTA) treatment, measurement of C1q or C3d binding and/or their intragraft detection [graft-bound donor-specific antibody (gDSA)]. We aimed to investigate which of these markers best associates with antibody-mediated rejection (ABMR) and kidney allograft loss at the time of a for-cause biopsy.

Methods: This retrospective, single-centre study included 77 kidney transplant recipients who underwent a for-cause biopsy between December 2004 and July 2013. All displayed serum DSAs were identified on the same day as the biopsy. Sera were tested in parallel with the classical SAFB assay with or without serum EDTA treatment, C1q- and C3d-binding assays. gDSAs were eluted from biopsy fragments and identified with SAFB.

Results: The median time between transplantation and biopsy was 25 months (range 0.5-251). The median follow-up was 36 months (range 0-140). ABMR was histologically proven in 40% of recipients. The sensitivity and specificity of C1q, C3d and gDSA assays for predicting ABMR were 68% and 61%, 52% and 70% and 64.5% and 56.5%, respectively. At the time of biopsy, only the DSA MFI after EDTA treatment and C3d positivity were associated with graft loss. In multivariate analyses, glomerular filtration rate, transplant glomerulopathy and C4d positivity were the only factors associated with graft loss.

Conclusions: Our findings weaken the rationale for systematically implementing C1q, C3d or gDSA assays in this situation, because they do not independently predict ABMR and graft loss.
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http://dx.doi.org/10.1093/ndt/gfy088DOI Listing
October 2018

CD4+ T Cell Help Is Mandatory for Naive and Memory Donor-Specific Antibody Responses: Impact of Therapeutic Immunosuppression.

Front Immunol 2018 19;9:275. Epub 2018 Feb 19.

French National Institute of Health and Medical Research (INSERM) Unit 1111, Lyon, France.

Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)-producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression. Using murine models, we confirmed that heart transplantation, but not skin grafting, is associated with accumulation of a high quantity of alloantigens in recipients' spleen. Nevertheless, neither naive nor memory DSA responses could be observed after transplantation of an allogeneic heart into recipients genetically deficient for CD4+ T cells. These findings suggest that DSA generation rather result from insufficient blockade of the helper function of CD4+ T cells by therapeutic immunosuppression. To test this second theory, different subsets of circulating T cells: CD8+, CD4+, and T follicular helper [CD4+CXCDR5+, T follicular helper cells (Tfh)], were analyzed in 9 healthy controls and 22 renal recipients. In line with our hypothesis, we observed that triple maintenance immunosuppression (CNI + MMF + steroids) efficiently blocked activation-induced upregulation of CD25 on CD8+, but not on CD4+ T cells. Although the level of expression of CD40L and ICOS was lower on activated Tfh of immunosuppressed patients, the percentage of CD40L-expressing Tfh was the same than control patients, as was Tfh production of IL21. Induction therapy with antithymocyte globulin (ATG) resulted in prolonged depletion of Tfh and reduction of CD4+ T cells number with depleting monoclonal antibody in murine model resulted in exponential decrease in DSA titers. Furthermore, induction with ATG also had long-term beneficial influence on Tfh function after immune reconstitution. We conclude that CD4+ T cell help is mandatory for naive and memory DSA responses, making Tfh cells attractive targets for improving the prevention of DSA generation and to prolong allograft survival. Waiting for innovative treatments to be translated into the clinical field ATG induction seems to currently offer the best clinical prospect to achieve this goal.
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http://dx.doi.org/10.3389/fimmu.2018.00275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825980PMC
April 2019

Endothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejection.

J Clin Invest 2018 01 20;128(1):219-232. Epub 2017 Nov 20.

French National Institute of Health and Medical Research (INSERM) Unit 1111, Lyon, France.

Humoral rejection is the most common cause of solid organ transplant failure. Here, we evaluated a cohort of 49 patients who were successfully grafted with allogenic islets and determined that the appearance of donor-specific anti-HLA antibodies (DSAs) did not accelerate the rate of islet graft attrition, suggesting resistance to humoral rejection. Murine DSAs bound to allogeneic targets expressed by islet cells and induced their destruction in vitro; however, passive transfer of the same DSAs did not affect islet graft survival in murine models. Live imaging revealed that DSAs were sequestrated in the circulation of the recipients and failed to reach the endocrine cells of grafted islets. We used murine heart transplantation models to confirm that endothelial cells were the only accessible targets for DSAs, which induced the development of typical microvascular lesions in allogeneic transplants. In contrast, the vasculature of DSA-exposed allogeneic islet grafts was devoid of lesions because sprouting of recipient capillaries reestablished blood flow in grafted islets. Thus, we conclude that endothelial chimerism combined with vascular sequestration of DSAs protects islet grafts from humoral rejection. The reduced immunoglobulin concentrations in the interstitial tissue, confirmed in patients, may have important implications for biotherapies such as vaccines and monoclonal antibodies.
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http://dx.doi.org/10.1172/JCI93542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749508PMC
January 2018