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Introduction La survenue d’un rejet humoral, c’est-a-dire medie par l’apparition d’anticorps specifiques du donneur (DSA), represente desormais la premiere cause de perte de transplant renal. Les protocoles de traitement actuels, associant la plasmapherese et l’administration d’immunoglobulines polyvalentes a une majoration de l’immunosuppression de base permettent uniquement de ralentir la progression inexorable vers l’insuffisance renale terminale, avec une efficacite tres variable selon les individus. Evaluer correctement la reponse au traitement est un element pronostique indispensable de la strategie de surveillance du patient atteint de rejet humoral, et permet de guider l’utilisation des traitements de seconde ligne. Description Quatre-vingt-un patients traites pour un rejet humoral aigu entre 2004 et 2017, avec une biopsie de controle post-traitement disponible, ont ete inclus dans une etude retrospective bicentrique (centre hospitaliers universitaires de Lyon et Strasbourg). Methodes L’evolution apres traitement des parametres de suivi cliniques, histologiques et immunologiques a ete analysee. Resultats L’evolution des lesions de rejet humoral sur la biopsie (disparition, persistance ou progression) correlait avec le risque de perte du transplant renal (Logrank test, p = 0,001). Les patients dont les lesions ont disparu avaient une survie du transplant d’environ 80 % a 10 ans. Les patients qui avaient une persistance ou une progression des lesions histologiques sur la biopsie de controle apres traitement avaient un risque plus eleve de perte du transplant (HR : 3,91, p = 0,04 ; HR : 5,15, p = 0,02 respectivement). Aucun des parametres non invasifs habituellement utilises apres traitement pour surveiller l’intensite de la reponse humorale (evolution de la MFI du DSA immunodominant) ou le declin de la fonction renale (perte de DFG, persistance d’une proteinurie) n’a permis de predire l’evolution des lesions histologiques ( Fig. 1 ). Conclusion La surveillance invasive de l’evolution des lesions humorales par une biopsie de controle quelques mois apres traitement du rejet humoral aigu est un outil fiable pour predire la survie du greffon a long terme.

In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its sixth annual workshop series in September 2015 in Lille. This event brought together practitioners from across the country with the purpose of offering careful analysis of published studies on clinical practice issues that remain to be disputed. This article addresses the impact of HLA and KIR gene polymorphism on the outcome of the transplantation in order to optimize unrelated donor selection.

Production of de novo DSA (dnDSA) is associated with an increased risk of antibody mediated rejection after liver transplantation. Antibodies not only recognize the entire antigen but are able to bind specific functional epitopes present on the HLA molecule surface. The HLAMatchmaker and the PIRCHE-II (predicted indirectly recognizable HLA epitopes) algorithms are able to determine predictive epitope mismatches scores and de novo DSA (dnDSA) synthesis based on alloreactive eplets' identification. The aim of the present study was to assess, for the first time in liver transplantation, the complementarity between these two algorithms. We retrospectively analyzed a cohort of 407 adult and 133 pediatric liver transplant patients without preformed DSA, transplanted between 1991 and 2019 in Lyon and Montpellier. HLA antibodies were detected by single antigen bead assay. HLA typing of the donor-recipient pair was achieved by serological and/or DNA-based techniques. PIRCHE-II and HLAMatchmaker algorithms were then applied on both groups. During follow-up, 27.3% of adults and 38.3% of children developed dnDSA. HLA-DRB1 and DQB1-PIRCHE-II and HLAMatchmaker scores were significantly higher in dnDSA group compared to no DSA group for both pediatric and adult patients (except for PIRCHE-II HLA-DRB1 locus score in pediatrics). ROC curves allowed determining score thresholds classifying patients in low- and high-risk of dnDSA synthesis. The two algorithms' Kaplan-Meier curves showed a predicted incidence of dnDSA 20 years after transplantation significantly lower in the low-risk group compare with the high-risk group (log rank \textless0.05), in both cohorts, with a good negative predictive value. In conclusion, HLAMatchmaker and PIRCHE-II algorithms both are effective tools to identify anti-HLA immunization risk and to predict dnDSA formation after liver transplantation.

International audience

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., ‘Missing self’ is a mode of natural killer (NK) cell activation aimed to detect the lack of HLA-I molecules on infected or neoplastic cells. Here, the authors show that mismatch between donor HLA-I and cognate receptors on recipient NK cells mediates microvascular inflammation-associated graft rejection, a pathology that is preventable by mTOR inhibition.

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.

International audience

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.

Introduction Les troubles lymphoproliferatifs post-transplantation (PTLD) regroupent des pathologies heterogenes allant de proliferations lymphocytaires benignes a des lymphomes malins de haut grade. La majorite des PTLD provenant de cellules B, peu de donnees sont disponibles sur les PTLD a cellules T/NK (PTLD T/NK) Methodes Tous les cas de PTLD diagnostiques entre 1998 et 2007 dans les 35 centres de transplantation renale francais ont ete colliges prospectivement dans le registre national. Pour s’assurer de l’exhaustivite du recueil, les donnees du registre ont ete croisees avec celles de 2 bases de donnees independantes. Les donnees cliniques ces cas ont ete examinees et comparees a celles i) des 440 cas de PTLD a cellules B du registre et ii) d’une cohorte de 148 lymphomes a cellules T/NK « classiques ». Resultats obtenus ou attendus Un total de 58 cas de PTLD T/NK ont ete identifies. Les PTLD T/NK sont apparus significativement plus tard apres la transplantation et avaient une survie globale inferieure a celle des PTLD a cellules B (p Conclusion Les lymphomes T/NK systemiques sont un sous-type rare de PTLD ayant un pronostic tres sombre, probablement en raison d’un traitement sous-optimal et/ou de l’impact nefaste de l’immunosuppression therapeutique.

Introduction Le rejet medie par les anticorps (AMR) est une cause majeure de perte d’organe en transplantation. Pourtant, certains patients conservent une bonne fonction du greffon au long cours, malgre la presence d’anticorps specifiques du donneur (DSA) dans leur circulation. L’identification des parametres associes a la pathogenicite des DSA est donc aussi importante que la detection de leur presence. Des etudes experimentales recentes ont montre que la teneur en sucre, en particulier l’etat de sialylation du fragment Fc des IgG, est variable. Cela pourrait modifier la capacite des IgG a se lier au recepteur C1q et au recepteur Fc, modulant ainsi les fonctions effectrices des IgG. Dans cette etude, le statut de sialylation des DSA a ete analyse et sa relation avec la physiopathologie de l’AMR evaluee. Methodes Parmi les 938 greffes renaux ayant beneficie d’une biopsie du greffon entre 2004 et 2012 au CHU de Lyon, 69 remplissaient les criteres diagnostiques d’AMR. Les serums collectes au moment de la biopsie ont ete testes pour la presence de DSA par luminex. Le niveau de sialylation des DSA presents dans chaque serum a ete determine par chromatographie avec l’agglutinine de Sambucus nigra. Resultats obtenus ou attendus Tous les patients avaient des niveaux de sialylation des IgG seriques remarquablement similaires (∼ 2 %). Cependant, le statut de sialylation des DSA etait tres variable (mediane = 9 % ; range = 0–100 %), permettant de repartir les patients en deux groupes : DSA fortement sialyles : n = 44 (64 %) et faiblement sialyles : n = 25 (36 %). Les deux groupes ne differaient ni par l’intensite des lesions de rejet (C4d, ptc et g ; p > 0,05), ni par les taux de survie du greffon (Log rank test ; p = 0,99). Ces resultats cliniques ont ete confirmes in vitro dans les tests de cytotoxicite dependante du complement et de l’ADCC ( Fig. 1 ). Conclusion Le statut de sialylation des DSA est tres variable mais ne correle pas avec leur pathogenicite.

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

We have conducted a retrospective study on 251 patients from three centers in France and Switzerland between 2004 and 2010 with the goal to evaluate the impact of HLA-DRB3/B4/B5 allele mismatching after HLA-10/10-matched unrelated allogeneic hematopoietic stem cell transplantation (HSCT). Fourteen (5.5%) patients receiving HSCT from an HLA-10/10-matched unrelated donor had a mismatched DRB4 donor, 23 (9.5%) patients had a mismatched DRB3 donor and 214 (85%) had a fully matched unrelated donor (HLA-10/10) without DRB3- or DRB4-mismatched donor. We compared the outcomes of 37 patients with a DRB3 or DRB4 mismatch with the rest of the population. The median survival for a patient without DRB3/4 mismatch was 18 months (95% confidence interval (CI), 13-29), for DRB3-mismatched patients 32 months (95% CI, 13-NR) and for DRB4-mismatched patients 7 months (95% CI, 3-NR). The multivariate analysis showed a significant impact of DRB4 mismatching on survival (Hazards ratio (HR)=2.1 (95% CI, 1.01-4.67), P=0.045), acute GvHD (HR=2.66 (95% CI, 0.99-7.09) P=0.05) and on transplant-related mortality (HR=2.8; (95% CI, 1.7-4.4) P=0.024). In the view of an impact of DRB4 locus mismatch on clinical outcome, it would be important to confirm this observation in a prospective study as it may be worth considering DRB4 in the unrelated donor selection.

International audience; Matching for HLA‐A, ‐B, ‐C, and ‐DRB1 loci (8/8 match) is currently the gold standard for unrelated donor hematopoietic cell transplantation (HCT). In Europe, patients are also matched at the HLA‐DQB1 loci (10/10 match). However, there is increasing evidence that matching at HLA‐DRB3/4/5 loci may help to lower transplant‐related morbidity and mortality. We therefore investigated the impact of HLA‐DRB3/4/5 mismatches on outcomes in 1975 patients who received a first 10/10 matched unrelated donor (MUD) HCT in France from 2000 to 2012 for a hematological malignancy. High‐resolution typing was performed at HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, ‐DPB1, and ‐DRB3/4/5 loci for all donor/recipient pairs. Compared with DRB3/4/5‐matched pairs, patients who received a MUD HCT from a DRB3/4/5 mismatched donor had a significantly increased risk of grade II‐IV acute graft‐versus‐host disease (aGVHD) (Adjusted Hazard Ratio (HR) 1.43 (1.07 to 1.90)) associated with lower graft‐versus‐host disease‐free and relapse‐free survival (GRFS) (Adjusted HR 1.20 (1.02 to 1.42)). Conversely, we observed no differences in terms of chronic GVHD, nonrelapse mortality, relapse and overall survival. However, we believe that patients stand to benefit from DRB3/4/5 loci being considered for unrelated donor selection to improve GRFS and then quality of life after unrelated HCT.

Chimerism analysis is an important step for the patient follow-up after hematopoietic stem cell transplantation. It is used to quantify the donor and the recipient part of a cell population issued from blood or bone marrow sample. In addition to hemogram, this technique is necessary to appreciate the quality of engraftment. The aim of this article is to propose some recommendation about methods, result analysis and therapeutic decision in hematopoietic stem cell transplantation for malignant or non-malignant diseases.

International audience

BACKGROUND Single antigen flow beads assays may overestimate sensitization because of the detection of supposedly irrelevant antibodies recognizing denatured class I human leukocyte antigens (HLAs). METHODS Sera of 323 HLA-sensitized kidney transplant candidates positive with a class I HLA single antigen flow beads assay were retested after acid treatment of the beads. Denatured HLA antibodies were identified according to ratio between the measured fluorescence intensity for treated and nontreated beads. T-lymphocyte flow cytometry crossmatches were performed to characterize the ability of these antibodies to recognize HLA on normal cells as a surrogate of their potential clinical relevance. Their impact on organ allocation was evaluated through a calculated panel reactive antibody. The utility of single antigen flow beads largely devoid of denatured HLA (iBeads) was also evaluated. RESULTS Denatured HLA antibodies were detected in 39% of the patients. They provided much less positive flow cytometry crossmatches than anti-native HLA antibodies (16% vs. 83%, P

Within the framework of the EU-funded HLA-NET action, an analysis of three G-group alleles, HLA-B*44:02:01G, DRB1*14:01:01G and DQB1*03:01:01G, was undertaken in 12 European populations. Ambiguities were resolved by polymerase chain reaction-sequence-specific amplification (PCR-SSP) or PCR-sequence-based typing (PCR-SBT) in a total of 5095 individuals. The results of the DRB1*14:01/14:54 ambiguity showed high relative ratios (24–53%) of DRB1*14:01 in Bulgarians, Croatians, Greeks, Italians and Slovenians, contrasting with low ratios (6–13%) in Austrians, Finnish, French, Hungarians, Norwegians and Swiss. Resolution of the B*44:02/44:27 ambiguity showed that B*44:27 had a high relative ratio in Slovenians (25.5%) and Bulgarians (37%) and low in French and Swiss (0.02–1%), and was not observed in Greeks and Italians. The highest relative ratio of DQB1*03:19 was found in Portuguese (11%), by contrast with low ratios (0–3%) in the other five populations. Analysis of the A, B, DRB1 phenotypes and family-derived haplotypes in 1719 and 403 individuals positive for either HLA-B*44:02G or DRB1*14:01G ambiguities, respectively, showed some preferential associations, such as A*26∼DRB1*14:01, B*35∼DRB1*14:01, B*38∼DRB1*14:01 and B*44:27∼DRB1*16. Because these ambiguities are located outside the peptide-binding site, they may not be recognized by alloreactive T-cells. However, because of strong linkage disequilibrium (LD), the DRB1*14:01 vs DRB1*14:54 and the B*44:02 vs B*44:27 mismatches are associated to DRB3-, and C-mismatches, respectively. These results are informative for algorithms searching unrelated hematopoietic stem cell donors. For B*44:27-positive patients, searches are expected to be more successful when requesting donors from Southeastern-European ancestry. Furthermore, the introduction of human leukocyte antigen (HLA)-typing strategies that allow resolving exon 4 (for class I) and exon 3 (for class II) polymorphisms can be expected to contribute significantly to population genetics studies.

Introduction Si le rejet humoral (RH) est largement reconnu comme la 1re cause de perte des greffons son pronostic individuel est heterogene, rendant difficile l’evaluation du risque de perte de greffon au moment du diagnostic. Au cours du RH, la fixation des anticorps anti-donneur (DSA) a la surface des vaisseaux du greffon permet le recrutement de cellules de l’immunite innee (en particulier les cellules NK (NK)). Ces dernieres sont capables de leser les cellules endotheliales du greffon par un mecanisme de cytotoxicite dependante des anticorps (ADCC). Les NK interagissent avec le fragment Fc des DSA par un unique recepteur : le FcγR3A (CD16A). Un SNP (Fcγ RIIIa * 559A > C, rs396991) modulant l’affinite du FcγR3A pour le Fc des IgG a ete identifie mais son impact au cours du RH est inconnu. Methodes Parmi les transplantes renaux de notre centre ayant eu une biopsie de leur greffon entre 2004 et 2015, 118 presentaient un RH selon la definition de Banff : presence de i) lesions d’inflammation microvasculaire sur la biopsie, et ii) DSA dans la circulation. Resultats obtenus ou attendus 15,9 % des patients etaient homozygotes pour l’allele associe a une haute affinite du FcγR3A pour les IgG. Ces derniers presentaient une survie reduite du greffon par rapport aux patients ayant un FcγR3A de faible affinite (p = 0,03). Un modele in vitro humain d’ADCC entre des NK et des cellules endotheliales primaires recouvertes d’anticorps anti-HLA a confirme que les NK de donneurs ayant un FcγR3A de haute affinite s’activaient plus fortement et provoquaient davantage de dommages endotheliaux a un niveau equivalent de DSA. Conclusion Notre travail demontre que le polymorphisme du FcγR3A influe sur la severite du RH et suggere que ce parametre pourrait etre utilise comme un biomarqueur genetique de stratification du risque de perte de greffon au moment du diagnostic de RH.

Introduction En transplantation renale (TR), l’apparition de DSA de novo (DSAdn), la survenue d’un rejet et d’une perte de greffon (PG) sont associes a la non-adherence (NA). Trouver un outil de mesure prospectif de la NA utilisable en consultation, capable de predire ces evenements, est primordial. Methodes La NA etait mesuree a 3, 6, 12 et 24 mois post-transplantation par l’echelle de Morisky chez des adultes transplantes renaux precedemment inclus dans l’etude francaise sur la NA. Les residuelles d’anticalcineurines (CNI) etaient recueillis aux memes temps. L’impact de la NA et du regime de CNI sur le risque de PG defini par le premier evenement parmi le deces, la remis en dialyse ou une nouvelle TR, ont ete etudies par des modeles de Cox multivaries, avec variables dependantes du temps. L’impact de la NA et du regime de CNI sur l’apparition des DSAdn ont ete etudies par des modeles de regression logistique multivaries. Resultats obtenus ou attendus Trois cent un patients ont ete inclus et suivi pendant 10 ans. A 24 mois post-TR, les patients sans CNI avaient un risque significativement augmente d’apparition de DSAdn compare aux patients avec CNI (OR 6.09 ; IC95 % 1,24–30,0). Aucune difference significative n’etait retrouvee entre les patients adherents et NA a n’importe quel temps post-TR. Concernant le risque de PG, celui-ci n’etait statistiquement pas different entre les patients adherents et NA, quel que soit le temps de mesure mais on retrouvait une augmentation significative de ce risque chez les patients sans CNI ou avec des residuelles basses de CNI a 24 mois compares aux patients avec un regime standard (RR 2,36 ; IC95 % 1,40–6,67). Conclusion La NA mesuree par auto-questionnaire, dans les deux premieres annees de la greffe, n’est pas associee a l’apparition de DSA de novo, de rejet aigu ou de PG.

Introduction La generation de DSA (Donor Specific Antibodies) de novo post-transplantation est une cause majeure de perte de greffons. Le dogme immunologique soutient que la differenciation des lymphocytes B allospecifiques du receveur en plasmocytes producteurs de DSA necessite l’aide des T CD4+ du receveur de specificite indirecte, c’est-a-dire capables de reconnaitre les complexes « CMH (Complexe Majeur d’Histocompatibilite)-II du receveur/alloantigene » presentes a la surface du B allospecifique. Methodes A l’aide d’un travail translationnel, nous bousculons ce dogme et apportons la preuve que des T CD4+ provenant du donneur sont capables d’apporter l’aide aux B allospecifiques par la reconnaissance directe des molecules CMHII a leur surface et ainsi d’entrainer la production de DSA. Resultats obtenus ou attendus Bien que depourvues de lymphocytes T CD3+, les souris C57BL6 CD3ɛKO developpent une reponse DSA rapide (mais transitoire) apres transplantation d’un cœur CBA incompatible pour le CMH (H2k). Les lymphocytes T CD4+ peuvent etre isoles des cœurs de souris CBA et sont efficacement depletes par l’administration d’anticorps monoclonaux anti-CD3 ou anti-CD4. La depletion des lymphocytes T chez le donneur abroge la generation de DSA chez la souris receveuse CD3ɛKO. L’interaction entre les lymphocytes T du donneur (CBA) et les B du receveurs (C57BL6) a ete exploree in vitro, permettant d’eclaircir les mecanismes moleculaires impliques dans cette voie non-canonique de generation des DSA. Finalement, la pertinence clinique de nos resultats experimentaux est suggeree par la presence de lymphocytes du donneur dans les liquides de perfusion de greffons renaux, y compris des T helper folliculaires. Conclusion Notre travail montre que, en plus des lymphocytes T CD4+ du receveur de specificite indirecte, les T CD4+ du donneur transplantes avec le greffon sont capables d’apporter l’aide aux B allospecifiques du receveur par un mecanisme « direct inverse », jusqu’a present ignore.

Introduction La transplantation d’organe est le meilleur traitement en cas de defaillance terminale d’un organe vital. Cependant, la survie au long cours des greffon reste limitee par la perte inexorable de fonction, que le dogme immunologique actuel met sur le compte de l’inflammation microvasculaire causee par la reponse humorale allo-immune. Methodes L’analyse de 129 transplantes renaux presentant une inflammation microvasculaire sur la biopsie de greffon a demontre l’absence d’allo et d’auto-anticorps dans la moitie des cas. Chez ces patients, des etudes genetiques ont revele une prevalence plus elevee de « mismatches » entre les molecules HLA de classe I (HLA-I) du donneur et les « Killer-cell immunoglobulin-receptors » (KIR) inhibiteurs des cellules NK du receveur. Resultats obtenus ou attendus Nous avons emis l’hypothese que la nature allogenique de l’endothelium du greffon pouvait parfois creer un « pseudo-missing-self », responsable d’un rejet medie par les cellules NK. Pour demontrer cette hypothese, des co-cultures de cellules endotheliales et de NK humains ont ete realisees. Dans ce modele, l’absence du ligand HLA-I du soi sur la cellule endotheliale conduit a l’activation des NK qui deviennent capables de leser ces cellules endotheliales. Enfin, l’existence des rejets NK induit par le « missing-self » a ete demontree in vivo dans un modele murin de transplantation cardiaque. Conclusion Notre travail identifie un nouveau type de rejet chronique, exclusivement medie par l’immunite innee (les cellules NK), ayant le meme impact deletere sur la survie des greffons que le rejet humoral chronique.

International audience; Antibody-mediated rejection is associated with heterogeneous kidney allograft outcomes. Accurate evaluation of risk for graft loss at time of diagnosis is necessary to offer personalized treatment. In contrast with serological and molecular assessment, morpho-histological evaluation of antibody-mediated rejection lesions has not significantly evolved. This relies on Banff classifications designed to be of diagnostic discriminatory power rather than prognostic and face quantitative and qualitative limitations. Here we developed a method of Computer-assisted Analysis of Graft Inflammation (CAGI) to improve the classification of allograft inflammation. Digitization of immunostained biopsy sections, image processing and algorithm-driven analysis allowed quantification of macrophages, T cells, B cells, and granulocytes per unit surface of interstitium, capillaries or glomeruli. CAGI was performed on biopsy specimens of 52 patients with extensively phenotyped antibody-mediated rejection. Macrophage numbers in capillaries and interstitium, but not Banff scores or the amount of other immune cell subsets, correlated with donor-specific antibody (DSA) mean fluorescence intensity and DSA-C3d status. The quantity of macrophages in the interstitium and DSA-C3d status were the only independent predictors for significant allograft loss at the time of antibody-mediated rejection diagnosis (hazard ratio 3.71 and 2.34, respectively). A significant strategy integrating the DSA-C3d assay and the quantification of interstitial macrophages allowed identification of three groups with distinct renal prognosis: DSA-C3d-, DSA-C3d+/macrophages-low and DSAC3d+/macrophages-high. Thus, CAGI brings a missing piece to the antibody-mediated rejection puzzle by identifying morpho-histological processes that bridge in~vitro parameters of DSA pathogenicity and graft loss. Hence, this approach could be useful in future integrated strategies of risk evaluation.

International audience; In the absence of an HLA matched familial donor, a search for an unrelated donor or cord blood unit is initiated through worldwide registries. Although a first look-up on available HLA information of donors in the "book" at BMDW (Bone Marrow Donor Worldwide) can provide a good estimation of the number of compatible donors, the variety of resolution typing levels requires confirmatory typing (CT) which are expensive and time consuming. In order to help recipient centers in their work. The French donor registry (France Greffe de Moelle/Agence de la Biomedecine) has recently developed a software program called "EasyMatch(R)" that uses haplotype frequencies to compute the likelihood of phenotypic match in donors according to various typing resolution levels. The goal of our study is to report a single monocentric user-experience with EasyMatch(R), demonstrating that its routine use reduced the cost and the delay of the donor search in our center, allowing the definition of a new strategy to search compatible unrelated donors. The strategy was first established on a retrospective cohort of 217 recipients (185 adults and 32 children=before score) and then validated on a prospective cohort of 171 recipients (160 adults and 11 children=after score). For all patients, we calculated the delay between the registration day and the donor identification day, and the number of CT requested to the donor centre. Considering both groups, we could observe a significant decrease of the number of CT from 8 to 2 (p\textless0,001), and a significant decrease of the median delay to identify a suitable donor from 43 to 31days (p\textless0.0001). EasyMatch(R) estimates the number of potentially identical donors, but doesn't foresee availability of the donors. It provides us an easy tracking of mismatches, an estimation of the number of potential donors, the selection of population following ethnic origin of patients and a high prediction when probability is high or low. It affords a new approach of donor search in our daily work and improves the efficiency in the great challenge of the compatible donor identification

In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its sixth annual workshop series in September 2015 in Lille. This event brought together practitioners from across the country with the purpose of offering careful analysis of published studies on clinical practice issues that remain to be disputed. This article addresses the impact of HLA and KIR gene polymorphism on the outcome of the transplantation in order to optimize unrelated donor selection.

Lymphodepletive agents play important role in different clinical applications or experimental transplant studies. In order to facilitate preclinical pediatric transplant studies, we have developed the rabbit anti-pig thymocyte globulin (pATG) and studied its effects in neonatal swines. In vitro assays showed that pATG can bind to lymphocytes and neutrophils in a dose-dependent manner and lyse peripheral blood mononuclear cells by apoptosis and complement-dependent cytotoxicity. In vivo, pATG as a monotherapy was administered at different doses (2.5, 5, 20, 40 and 80mg/kg) in newborn pigs. Results showed that pATG induced a dose-dependent but transient T-cell depletion in peripheral blood. Lymphodepletion was also observed in lymph nodes, spleen and thymus. Pharmacokinetic studies showed dose-related cell-bound pATG on lymphocytes, as well as the presence of free pATG in the serum. Both cell-bound and free pATG levels decreased gradually after administration. Interestingly, adjuvant mycophenolate mofetil (MMF) given at 1g/m2/day for 1week successfully maintained pATG-induced T-cell depletion. In conclusion, pATG administration can cause transient T-cell depletion in neonatal pigs and this effect can be maintained by MMF. Therefore, we have developed an original immunosuppressive regimen that can be used for transplantation studies in swine model.

Resume L’introduction des dosages en phase solide pour la detection des anticorps anti-HLA en routine a entraine l’application de nouveaux algorithmes pour le suivi immunologique des patients candidats a la transplantation renale et a permis d’eviter de nombreux cas de rejet, qu’il n’aurait pas ete possible de deceler en utilisant les techniques serologiques dependantes du complement. Dans le present travail, nous avons fait une etude comparative entre deux techniques de depistage des anticorps anti-HLA, ELISA et Luminex ® . Les donnees du Luminex ® ont ete analysees de deux facons, avec le seuil de positivite du fournisseur et avec les nouveaux seuils etablis apres analyse des discordances et identification des anticorps. Au terme de cette etude, nous pouvons dire que les deux techniques sont tres sensibles. Toutefois, la technologie Luminex ® est plus specifique et plus rapide.

Resume Le transfusion-related acute lung injury (trali), œdeme pulmonaire lesionnel aigu post-transfusionnel), bien que son incidence soit probablement mesestimee, apparait toujours comme l’une des premieres causes residuelles de mortalite transfusionnelle. Il s’agit d’un veritable œdeme lesionnel pulmonaire survenant au decours de la transfusion de produits d’apherese ou de concentres erythrocytaires. Son mecanisme physiopathologique resulte d’un conflit immunologique par infusion d’anticorps du donneur diriges vis-a-vis des leucocytes. Il peut s’agir aussi de la transfusion passive de metabolites accumules dans le produit transfuse, tels des lipides activateurs des neutrophiles et des cellules endotheliales. Les interventions de l’immunite innee et de l’inflammation par les kinines vasoactives sont predominantes. La connaissance de son etiopathogenie doit faire acceder a l’amelioration de la prevention, a son meilleur diagnostic et a la prise en charge du patient adaptee.

Determination of minimal residual disease (MRD) remains crucial for the follow-up after therapy in chronic lymphocytic leukemia (CLL) patients. Chimerism was assessed by short tandem repeat (STR)-PCR and single nucleotide polymorphisms (SNP)-PCR, and MRD by a multicolor flow cytometric approach in 12 consecutive patients with CLL after they received allogeneic stem cell transplantation (SCT). Overall, 11 patients achieved MRD flow negativity [10 had full donor chimerism (FDC) and one had mixed chimerism (MC)]. Only one patient remained with MRD flow positivity and displayed MC. Fifty-six samples were concomitantly studied by both chimerism and MRD flow. A significant correlation was observed between MRD flow data and chimerism in both PB and BM by using a mixed effect linear regression (p < 0.001). Flow cytometry approach of MRD can be easily combined with chimerism during the follow-up post-allogeneic SCT. Both techniques appeared complementary for guiding post-transplant immunomodulation.

We report the post-transplant lymphocyte subset recovery of 226 children treated with Unrelated Cord Blood transplant (UCBT) (n = 112) or Unrelated Bone Marrow Transplant (UBMT) (n = 114) for malignant or non-malignant diseases. Absolute numbers of natural killer (NK), B and T cells were monitored by flow cytometry up to 5 years post-transplant. Immunological endpoints were: time to achieve a CD 3+ cell count >0·5 and 1·5 × 10 9 /1, CD4 + > 0·2 and 0·5 × 10 9 /1, CD8 + > 0·25 × 10 9 /1, CD19 + > 0·2 × 10 9 /1, NK > 0·1 × 10 9 /1. These endpoints were analysed through the use of cumulative incidence curves in the context of competing risks. CD8 + T cell recovery was delayed after UCBT with a median time to reach CD8 + T cells > 0·25 x 10 9 /1 of 7·7 months whereas it was 2·8 months in UBMT (P 0·2 × 10 9 /1 of 3·2 months in UCBT and 6·4 months in UBMT (P = 0·03). Median time for CD4 + T cell and NK cell recovery was similar in UCBT and UBMT. CD4 + T cells recovery was negatively correlated to age (better reconstitution in younger patients, P = 0·002). CD8 + T cells recovery was shorter in recipients with a positive cytomegalovirus serology (P = 0·001 ).

Introduction Since recently, HLA typing of CP-CML patients (pts) ≤65 years old was still recommended in at diagnosis and treated by Imatinib (IM) first-line, especially in case of baseline warnings (Baccarani et al. 2006/2009/2013), in the aim of performing allo-transplant if TKI failure occurs. Additionally, HLA molecules are processing BCR-ABL peptides at the surface of leukemic cells and trigger immune response, exploitable in autologous (Bocchia Lancet 2005) and allogeneic (Fefer NEJM 1979; Kolb Blood 1995) settings, including in residual disease conditions. The performance of antigen processing might differ according to the type of HLA molecules involved, but this remains largely debatable. Aims 1) To analyse the frequency of HLA subtypes in CP-CML pts as compared to those of the general population. 2) To investigate if IM first-line response differ according to the HLA subtypes, suggesting an involvement of the autologous immune system in the response observed. Methods We retrospectively analyzed a cohort of newly diagnosed CP-CML pts treated with IM first-line 400 mg alone and HLA typed (generic and/or allelic) in our center between years 2000 and2018. All pts were followed according to the ELN recommendations 2006/2010/2013. Clinical data were extracted from medical files, and responses were analysed with standard methods. Molecular results were ELN standardised since 2003, and were expressed as BCR-ABLIS in %. Overall survival (OS), progression-free survival (PFS), failure-free survival (FFS: progression to advanced phases death, loss of CHR, CCyR, or MMR, discontinuation of IM for toxicity, primary cytogenetic resistance) were analysed since IM initiation in intention-to-treat. Results Eighty-three pts have been included, with a median age of 47.5 (11-64.8) years at diagnosis, with 58% males and 42% females. Sokal score (n=80) was low in 44%, intermediate in 42% and high in 14%. ACA were present at diagnosis in 7% of pts (NA in 3), 2 pts had a cryptic Ph, and 2 a variant Ph. Major BCR transcripts were found in 96.4% pts, and atypical transcripts in 3.6%. We compared the frequencies of HLA A, B, C and DR in our 83 CP-CML to those of 5,225 unrelated bone marrow donors (UBMD) typed in the registry of the Rhône-Alpes region (35 million inhabitants). We could demonstrate that the HLA B13, B28, B51, B53 were significantly over-represented in the CP-CML population vs UBMD (4.24 vs 2.02%; 3.63 vs 2.48%, 11.5 vs 8.53%, 1.82 vs 0.88, overall p value = 0.007, Monte-Carlo test) as well as C05 (13.75 vs 8.39%, p=0.044) respectively. In addition, HLA B27, B45 and B55 were underrepresented in CP-CML pts vs UBMD (0.60 vs 3.43%, 0 vs 0.6%, 0.6 vs 1.66%, p=0.007, Monte-Carlo test). There was no difference for HLA A, and DR antigens. All pts got IM (Glivec®) 400 mg daily since diagnosis. The median follow-up after IM initiation was 111.5 (7.6-203) months. CHR was reached after a median of 1 (0-3.5) month, Conclusions CP-CML seems overrepresented in some particular HLA subtypes, and the sensitivity of the disease to IM seems improved in the HLA DRB1 07 allele although not significant. Whether this is related to the biological function of HLA molecules at the surface of CML cells or to a specific genetic background of these pts needs to be determined. These findings need to be confirmed in larger ongoing series. Disclosures Nicolini: Sun Pharma: Consultancy; Incyte: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Hayette:Incyte: Consultancy. Michallet:Octapharma: Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy; Novartis: Research Funding.

To evaluate the influence of intragraft inflammatory infiltrate on the course of chronic rejection, 11 human renal grafts, detransplanted for terminal failure, were analyzed. Samples were divided into two groups according to their graft survival (> or ≤8 y). In both groups, the main cell population infiltrating the graft interstitia was T lymphocytes. The extent of the lymphocytic infiltration and the distribution of naive and memory, CD4+ and CD8+ T cells, were similar in both groups. Although all types of Th polarization profiles can lead to terminal chronic rejection, a correlation between shorter graft survival and the presence of Th17 cells that produce IL-17 and IL-21 was observed. In contrast, grafts infiltrated by regulatory T cells survived significantly longer. The correlation between the expressions of activation-induced cytidine deaminase (the key enzyme of the germinal center reaction) and IL-21 suggests that Th17 could exert their deleterious effect by promoting lymphoid neogenesis, namely, the organization of inflammatory effectors into ectopic germinal centers in which a local humoral immune response is elicited. Further studies will determine whether Th17 infiltration can be used as a prognosis tool and whether theTh17 subset constitutes a therapeutic target for slowing down chronic rejection.

Background Vascularized composite tissue allografts (VCA) can undergo rejection, manifesting pathologically with skin changes that form the basis of the Banff 2007 classification of VCA rejection. Methods We have followed 10 human VCA recipients (7 with hand allografts, 3 with face allografts) for pathological signs of rejection. All of them developed episodes of acute rejection. Two patients with hand allografts presented in some of their skin biopsies an as yet unreported pathological finding in human VCA, consisting of capillary thromboses (CT) in the upper dermis. Results Capillary thrombosis was associated with other typical changes of grade II to III VCA rejection, namely, perivascular T cell infiltrates, but not with vascular C4d deposits (in formalin-fixed tissue). Clinically, the lesions presented as red or violaceous (lichenoid) cutaneous maculopapules. The first patient had several episodes of acute rejection during the 7-year follow-up. The second patient developed donor-specific antibodies; some months after CT were first observed, he developed chronic rejection leading to partial amputation of the allograft. Pathological examination of the skin showed graft vasculopathy and occasional C4d deposits in cutaneous capillaries. Conclusions Capillary thrombosis seems to be a novel pathologic finding associated with human VCA rejection. Although its mechanism (immunologic vs nonimmunologic) remains unclear, this finding could carry an unfavorable prognostic significance, prompting close monitoring of the patients for severe/chronic rejection.

International audience; C1q-binding ability may indicate the clinical relevance of de novo donor-specific anti-HLA antibodies (DSA). This study investigated the incidence and risk factors for the appearance of C1q-binding de novo DSA and their long-term impact. Using Luminex Single Antigen Flow Bead assays, 346 pretransplant nonsensitized kidney recipients were screened at 2 and 5 years after transplantation for de novo DSA, which was followed when positive by a C1q Luminex assay. At 2 and 5 years, 12 (3.5%) and eight (2.5%) patients, respectively, had C1q-binding de novo DSA. De novo DSA mean fluorescence intensity \textgreater6237 and \textgreater10,000 at 2 and 5 years, respectively, predicted C1q binding. HLA mismatches and cyclosporine A were independently associated with increased risk of C1q-binding de novo DSA. When de novo DSA were analyzed at 2 years, the 5-year death-censored graft survival was similar between patients with C1q-nonbinding de novo DSA and those without de novo DSA, but was lower for patients with C1q-binding de novo DSA (P=0.003). When de novo DSA were analyzed at 2 and 5 years, the 10-year death-censored graft survival was lower for patients with C1q-nonbinding de novo DSA detected at both 2 and 5 years (P\textless0.001) and for patients with C1q-binding de novo DSA (P=0.002) than for patients without de novo DSA. These results were partially confirmed in two validation cohorts. In conclusion, C1q-binding de novo DSA are associated with graft loss occurring quickly after their appearance. However, the long-term persistence of C1q-nonbinding de novo DSA could lead to lower graft survival.

International audience; PURPOSE OF REVIEW: Vascularized composite allotransplantation (VCA) has several immunological peculiarities that imply a specific immune monitoring. Here, we provide an integrated view of current procedures of immune monitoring in VCA and potential complementary approaches learned from organ transplantation. RECENT FINDINGS: Because the skin is highly immunogenic and is the main target of the alloimmune response, immune monitoring in VCA essentially relies on visual inspection and pathological examination of for-causes and protocol skin biopsies. Light microscopical and immunohistochemical analyses enable us to identify skin lesions that are characteristic, but not specific, of allograft rejection. Complementary approaches of immunological assessment may assist in reinforcing the diagnosis of rejection and preventing over-immunosuppression or under-immunosuppression. Such approaches can inform either on the patient's global immune status or more specifically on the B-cell-mediated or T-cell-mediated immune responses against donor antigens. SUMMARY: Strategies that integrate both the current 'gold standards' of monitoring in VCA and a complementary multilayer immunological assessment are likely to provide the highest precision for the personalized determination of the recipients' immunological status. The objective is a tailored adaptation of immunosuppressive treatment.

International audience; Adoptive cell therapy represents a promising approach for several chronic diseases. This study describes an innovative strategy for biofunctionalization of nanoparticles, allowing the generation of synthetic particulate antigens (SPAg). SPAg activate polyclonal B cells and vectorize noncognate proteins into their endosomes, generating highly efficient stimulators for ex vivo expansion of antigen-specific CD4+ T cells. This method also allows harnessing the ability of B cells to polarize CD4+ T cells into effectors or regulators.

HLA matching between the donor and recipient improves the success of unrelated hematopoietic stem cell transplantation (HSCT). Because many patients in need of an unrelated transplant have only donors with mismatch, information is needed to evaluate the limits of HLA mismatching. We examined the association of survival, acute graft-versus-host disease (aGVHD) and relapse with HLA-A, -B, -C, -DRB, -DQB1, and -DPB1 mismatching in 334 patients coming from 12 French transplant centers and who received a non-T cell-depleted bone marrow graft from an unrelated donor. All patients were prepared with the use of myeloablative conditioning regimens. Our analyses demonstrate negative effects of HLA mismatching for either HLA-A, -B, -C, -DRB1, or -DQB1 loci on survival. Multivariate Cox analyses showed that a single mismatch was associated with a significant decrement in survival (P = .046, hazard ratio [HR] = 1.41, confidence interval [CI] 95% 1.1-1.98). The presence of multiple mismatches was worse for survival (P = .003, HR = 1.91, CI 95% 1.26-2.91) and severe aGVHD (grade III-IV) (P = .002, HR = 2.51, CI95% 1.41-4.46). The cumulative incidences of aGVHD and relapse in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with 2, 1, or 0 DPB1 incompatibilities were 63%, 50%, and 51%, and 12%, 27%, and 20%, respectively, but these differences were not statistically significant. Similar differences of aGVHD and relapse, but not statistically significant, were observed in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with DPB1 disparities classified into permissive or nonpermissive mismatches according to Zino’s classification based on a hierarchy of the immunogenicity of the HLA-DP molecules. “Missing killer cell immunoglobulin-like receptor (KIR) ligand” evaluated on the presence of HLA-C1, -C2, and Bw4 groups in the recipients was not associated with aGVHD, survival, and relapse in this cohort of non-T cell-depleted HSCT.

Graft-versus-host disease (GVHD) accounts for increased morbidity and mortality after HLA-identical unrelated hematopoietic cell transplantation (HCT). To test the hypothesis that the major histocompatibility complex (MHC) encodes functional variation other than the classical HLA genes, we measured risks associated with donor-recipient MHC microsatellite (Msat) marker mismatching in 819 HCT recipients and their HLA-A, -B, -C, -DRB1, and -DQB1 allele-matched unrelated donors. Suggestive trends of association with transplant outcome were observed for 5 Msats. Donor-recipient mismatching for the extended class I D6S105, class III D6S2787, and class II D6S2749 markers was each associated with an increased risk of death (hazard ratio, 1.32; 95% confidence interval, 1.02-1.71; P = .03; hazard ratio, 1.26; 95% confidence interval, 1.03-1.53; P = .02; hazard ratio, 1.37; 95% confidence interval, 1.08-1.72; P = .007, respectively) whereas mismatching for the class I D6S2811 marker was associated with a decreased risk of death (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P = .03). Mismatching for the class I D6S265 marker was associated with a decreased risk of grades III-IV acute GVHD (odds ratio, 0.67; 95% confidence interval, 0.45-0.98; P = .04). These results suggest that Msats may be informative for mapping MHC-resident genetic variation of clinical importance in HCT.

Objective: Diabetes is clinically classified into two types: type 1 (T1D) and type 2 diabetes (T2D). Nevertheless, intermediate forms of diabetes are frequent and difficult to recognize and manage appropriately. In this study, we investigated whether patients with intermediate form of diabetes, here called unclassified diabetes (UD), have β-cell autoimmune markers. Research design and methods: β-cell autoimmune markers (β-cell autoantibodies (aAb), peripheral blood mononuclear cells (PBMC) responsive to five islet proteins, cytokine secretion, and human leukocyte antigen (HLA)-DQB1 genotypes) were analyzed in 50 UD patients, 23 age- and HLA-matched normal control subjects, and 23 classic T2D patients. Results: We observed that 16 out of 50 (32%) UD patients demonstrated responsive PBMCs, as opposed to 1 out of 23 (5%) age- and HLA-matched normal control subjects, and 0 out of 23 classic T2D patients. Overall, 29 (58%) UD patients had at least one marker of β-cell autoimmunity (β-cell aAb and/or PBMC autoreactivity), in association with high-risk HLA genotypes DQB1*0201 and/or DQB1*0302. Moreover, the 13 (26%) UD patients who had β-cell aAb were not the same as those with PBMC autoreactivity, except for one patient. Patients with PBMC autoreactivity were older at the onset of the disease and had a better residual β-cell function than those with β-cell aAb. Conclusions: Our data confirm that T-cell autoimmunity can be detected in latent autoimmune diabetes in adults patients. We show an inverse correlation between humoral and cellular β-cell autoimmunities. Possible protective cellular responses in the patients with β-cell PBMC autoreactivity could have potential therapeutic implications.

International audience; PURPOSE OF REVIEW: As both the number of vascularized composite allotransplants (VCAs) recipients and the duration of their follow-up are limited, immunopathology of VCA rejection remains incompletely understood. VCAs have several immunological peculiarities, which make inaccurate a direct extrapolation of all rules established for solid organs. RECENT FINDINGS: Despite their bone marrow content, VCA do not induce chimerism in recipient and are therefore not spontaneously tolerated. Skin compartment of VCA contains a high density of antigen-presenting cells (APCs), some with self-renewal capacity. Donor APCs are responsible for continuous direct allosensitization of recipient's T cells that explains the high incidence of skin T-cell-mediated rejection and their occurrence beyond 1 year.Regenerative capability of the skin prevents the development of chronic rejection of this compartment as long as immunosuppression is maintained. In contrast, VCA can develop graft arteriosclerosis, which could be because of T cell and/or chronic antibody-mediated rejection (AMR). VCA recipients can indeed develop donor-specific antibodies (DSA). Whether DSA can also trigger acute AMR of VCA remains to be clarified. SUMMARY: A better understanding of the specificities of the immunopathology of VCA rejection should pave the way for the rationalization of immunosuppressive strategies aiming at optimizing long-term outcome.

Study Objectives: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. Methods: HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4,043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. Results: HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10−4), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10−3), and B*35:01 (OR = 1.46 [1.13-1.89] P = 3.64*10−3) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr9 (OR = 1.32 [1.15-1.52] P = 6.95*10−5) and HLA-C-Ser11 (OR = 1.34 [1.15-1.57] P = 2.43*10−4). Conclusions: Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons. Significance Although evidence strongly indicates that immune-related mechanisms are involved in the pathogenesis of narcolepsy with hypocretin deficiency, functional data are missing. The strong association with HLA class II genes is not corroborated by any CD4+ T Cell implication and inflammation. Additionally, these genes are not normally expressed in the brain. Here, we show that several HLA class I variants are associated with narcolepsy. Since these molecules are expressed in the brain, our results suggest that a cytotoxic (CD8+ T Cell or NK cell) mechanism might be the final step in the disease, leading to hypocretin neuronal destruction.

Overlooked for decades, antibodies have taken center stage in renal transplantation and are now widely recognized as the first cause of allograft failure. Diagnosis of antibody-mediated rejection has considerably improved with identification of antibody-mediated lesions in graft biopsies and advances made in the detection of circulating donor-specific antibodies. Unfortunately, this progress has not yet translated into better outcomes for patients. Indeed, in the absence of a drug able to suppress antibody generation by plasma cells, available therapies can only slow down graft destruction. This review provides an overview of the current knowledge of antibody-mediated rejection and discusses future interesting research directions.

Humoral rejection and its relationship with anti HLA antibodies have been extensively studied in organ transplantation with the exception of liver transplantation (LT). Recently, association between donor specific anti HLA antibodies (DSA) and increased risk of rejection and graft loss has been suggested in LT. When such antibodies appear, adequate treatment and monitoring are needed to avoid or delay allograft loss. We report here three cases of probable antibody-mediated rejection developed after pregnancy in liver transplanted women. Sera at the time of rejection and during follow-up have been retrospectively tested for the ability of DSA to bind complement components. These cases display different outcomes depending on the complement binding DSA capacity and titers after treatment of the rejection episodes. Thus, they highlight the potential interest of complement binding Luminex Single Antigen assays to monitor the efficiency of anti-rejection therapy.

We characterized three new HLA class I alleles: B*15:222, B*15:247 and B*27:92 found by routine typing.

Le passage du primaire au secondaire représente un stress pour la majorité des élèves, sans qu’ils le perçoivent pour autant comme une étape entièrement négative. Jusqu’à maintenant, aucune étude n’a examiné les liens entre les anticipations des élèves de sixième année du primaire à l’égard du secondaire et leur profil motivationnel. La présente étude vise à comprendre comment les anticipations positives et négatives chez 793 élèves sont liées à des variables particulières. Les analyses font voir que l’optimisme, la hâte d’aller au secondaire, les buts d’apprentissage et la conception de l’intelligence sont reliés aux anticipations positives. Les mêmes variables présentent aussi des liens avec les anticipations négatives, le sexe des élèves et leur sentiment d’efficacité., The transition between primary school and high school represents a stressing event for the majority of the students. However, they do not perceive that transition as an entirely negative experience. Until today, no study has focused on the relationship between six graders’ anticipations towards high school and their motivational profile. The main objective of the present study is to understand how the positive and negative anticipations of 793 pupils are related to particular variables. The results of the analyses show that optimism, the eagerness to go to high school, the learning goals and the conception of intelligence are connected to positive anticipations. Those same variables are also related to negative anticipations, as well as to pupils’ gender and their feeling of effectiveness., La transición de la primaria a la secundaria representa un acontecimiento estresante para la mayoría de los alumnos, sin por eso que lo vean como una etapa totalmente negativa. Hasta ahora, ningún estudio ha examinado las relaciones entre las anticipaciones de los alumnos de sexto grado de primaria hacia la secundaria y su perfil motivacional. El presente estudio tiene por propósito entender cómo las anticipaciones positivas y negativas en 793 alumnos son ligadas a variables particulares. Los resultados de los análisis demuestran que el optimismo, el deseo anticipado de llegar a la secundaria, las metas de aprendizaje y la concepción de la inteligencia son relacionados con anticipaciones positivas. Asimismo, las mismas variables presentan relaciones con las anticipaciones negativas, el sexo de los alumnos y su sentimiento de eficacia., Die Versetzung von der Grundschule zur Sekundarstufe erweist sich für die Mehrheit der Schüler als ein stressiges Ereignis, ohne daß es von ihnen als ein total negativer Abschnitt angesehen wird. Bis heute hat noch keine Studie die Zusammenhänge zwischen den Erwartungen der Schüler der sechsten Grundschulklasse im Hinblick auf die Sekundarstufe, und dem Motivationsprofil, untersucht. Die gegenwärtige Studie zielt darauf ab, zu verstehen, wie die positiven und negativen Erwartungen bei 793 Schulern mit besonderen Variablen zusammenhängen. Die Ergebnisse der Analyse zeigen, daß der Optimismus, die Eile in die Sekundarstufe zu gelangen, die Lernziele und die Intelligenzkonzeption an positive Erwartungen gebunden sind. Die gleichen Variablen zeigen auch den Zusammenhang mit negativen Erwartungen, dem Geschlecht der Schüler und ihr Empfinden fuer Leistungsfähigkeit.

This retrospective study aimed to analyse the impact on overall survival (OS) and event-free survival (EFS) of chimaerism status and kinetics following allogeneic conventional and reduced-intensity conditioning haematopoietic stem cell transplantation, and to compare this with the impact of other well-known factors. We investigated the chimaerism status of 187 patients [84 females, 103 males; median age 39.5 years (range, 17-62 years)]. After transplantation, 121 patients (65%) presented full donor chimaerism (FDC) and 63 (34%) mixed chimaerism (MC). For MC, we divided the population into patients who presented regressive mixed chimaerism (RMC) (21 patients: 11%), stable mixed chimaerism (SMC) (20 patients: 11%) and progressive mixed chimaerism (PMC) (22 patients: 12%). At last follow-up, 71 patients were alive and 116 had died (48% from disease progression and 52% from transplant-related causes). With a mean follow-up of 39.4 and 34.8 months, the 5-year probabilities of OS and EFS for the total group were, respectively, 55% and 43%: 69.5% and 61% for FDC, 35.4% and 25% for RMC, 42.6% and 28.6% for SMC, and 21% and 10.4% for PMC (P < 0.0001 and P < 0.0001). Multivariate analysis only showed a significant impact of chimaerism status on OS, as well as acute and chronic graft-versus-host disease on EFS, with a trend for conditioning regimen.