Publications by authors named "Valérie Dubois"

71 Publications

Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis.

Neurol Neuroimmunol Neuroinflamm 2021 May 5;8(3). Epub 2021 Mar 5.

From the French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., L.T., A.V., A.-L.P., G.P., C.B., L.-D.D., B.J., V.R., J. Honnorat), Hospices Civils de Lyon, Hôpital Neurologique, Bron, France; SynatAc Team (S.M.-C., L.T., A.V., A.-L.P., G.P., C.B., L.-D.D., B.J., V.R., J. Honnorat), Institut NeuroMyoGène, INSERM U1217/CNRS UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1, France; Clinic Research and Epidemiology Department (J. Haesebaert), Hospices Civils de Lyon, Lyon, France, HESPER Team, EA 7425, Medicine School, Université Claude Bernard Lyon 1, France; Neurology Department 2-Mazarin (G.B., D.P., A. Alentorn), Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, APHP; Brain and Spinal Cord Institute (G.B., D.P., A. Alentorn), INSERM U1127/CNRS UMR 7255, Université Pierre-et-Marie-Curie, Universités Sorbonnes, Paris, France; HLA Laboratory (V.D.), French Blood Service, EFS Auvergne-Rhône-Alpes, Lyon, France; Stanford University Center for Sleep Sciences and Medicine (A. Ambati, E.M.), Palo Alto, CA; and Department of Psychiatry (R.T.), Hôpitaux Universitaires Henri Mondor, Créteil, France, Mondor Institute for Biomedical Research, INSERM U955, Université de Paris-Est-Créteil, France.

Objective: Antibodies against leucine-rich glioma-inactivated 1 (LGI1-Abs) characterize a limbic encephalitis (LE) strongly associated with HLA-DRB1*07:01, although some patients lack LGI1-Abs in CSF or do not carry this allele. Whether they represent a different subtype of disease or have different prognoses is unclear.

Methods: Retrospective analysis of clinical features, IgG isotypes, and outcome according to LGI1-Ab CSF positivity and DRB1*07:01 in a cohort of anti-LGI1 LE patients.

Results: Patients with LGI1-Abs detected in both CSF and serum (105/134, 78%) were compared with those who were CSF negative (29/134, 22%). Both groups had similar clinical features and serum levels, but CSF-positive patients had shorter diagnostic delay, more frequently hyponatremia, inflammatory CSF, and abnormal MRI ( < 0.05). Human leukocyte antigen (HLA) genotyping was performed in 72/134 (54%) patients and 63/72 (88%) carried DRB1*07:01. Noncarriers (9/72, 12%) were younger, more commonly women, and had less frequently psychiatric and frontal symptoms ( < 0.05). No difference in IgG isotypes according to CSF positivity or HLA was found ( > 0.05). HLA and IgG isotypes were not associated with poor outcome (mRS >2 at last follow-up) in univariate analyses; CSF positivity was only identified as a poor outcome predictor in the multivariate analysis including the complete follow-up, whereas age and female sex also remained when just the first year was considered.

Conclusions: LE without CSF LGI1-Abs is clinically indistinguishable and likely reflects just a lesser LGI1-Ab production. HLA association is sex and age biased and presents clinical particularities, suggesting subtle differences in the immune response. Long-term outcome depends mostly on demographic characteristics and the intensity of the intrathecal synthesis.
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http://dx.doi.org/10.1212/NXI.0000000000000974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938443PMC
May 2021

Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis.

Brain 2021 Apr 12. Epub 2021 Apr 12.

French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France.

Limbic encephalitis (LE) with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leukocyte antigen (HLA), and CSF proteomic profiles. Patients with anti-AK5 LE were mostly men (20/26, 76.9%) of median age 66 years old (range 48-94). Predominant symptom was severe episodic amnesia in all patients, frequently associated with depression (17/25, 68.0%). Weight loss, asthenia, and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%), and increased Tau (11/14, 78.6%). Temporal lobe hyper-intensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably toward a severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with highest titres in nine CSF-serum paired samples. Temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T-cells, intense granzyme B expression, and abundant macrophages/microglia. HLA analysis in 11 patients showed a striking association with HLA-B*08:01 (7/11, 63.6%; OR = 13.4, 95% CI [3.8-47.4]), C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI [2.9-42.5]), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI [3.7-55.7]), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI [3.5-52.0]), and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI [3.7-55.7]) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI [4.8-57.1]). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 controls and 10 cases with other more common non-paraneoplastic LE (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed, respectively, 31 and seven significantly up-regulated proteins in anti-AK5 LE, mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 LE result from a distinct T-cell mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.
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http://dx.doi.org/10.1093/brain/awab153DOI Listing
April 2021

Massive clonal expansion of polycytotoxic skin and blood CD8 T cells in patients with toxic epidermal necrolysis.

Sci Adv 2021 03 19;7(12). Epub 2021 Mar 19.

Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France.

Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction. To better understand why skin symptoms are so severe, we conducted a prospective immunophenotyping study on skin and blood. Mass cytometry results confirmed that effector memory polycytotoxic CD8 T cells (CTLs) are the main leucocytes in TEN blisters at the acute phase. Deep T cell receptor (TCR) repertoire sequencing identified massive expansion of unique CDR3 clonotypes in blister cells. The same clones were highly expanded in patient's blood, and the degree of their expansion showed significant correlation with disease severity. By transducing α and β chains of the expanded clonotypes into a TCR-defective cell line, we confirmed that those cells were drug specific. Collectively, these results suggest that the relative clonal expansion and phenotype of skin-recruited CTLs condition the clinical presentation of cutaneous adverse drug reactions.
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http://dx.doi.org/10.1126/sciadv.abe0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978430PMC
March 2021

Data-driven Derivation and Validation of Novel Phenotypes for Acute Kidney Transplant Rejection using Semi-supervised Clustering.

J Am Soc Nephrol 2021 Mar 9. Epub 2021 Mar 9.

Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium

Background: Over the past decades, an international group of experts iteratively developed a consensus classification of kidney transplant rejection phenotypes, known as the Banff classification. Data-driven clustering of kidney transplant histologic data could simplify the complex and discretionary rules of the Banff classification, while improving the association with graft failure.

Methods: The data consisted of a training set of 3510 kidney-transplant biopsies from an observational cohort of 936 recipients. Independent validation of the results was performed on an external set of 3835 biopsies from 1989 patients. On the basis of acute histologic lesion scores and the presence of donor-specific HLA antibodies, stable clustering was achieved on the basis of a consensus of 400 different clustering partitions. Additional information on kidney-transplant failure was introduced with a weighted Euclidean distance.

Results: Based on the proportion of ambiguous clustering, six clinically meaningful cluster phenotypes were identified. There was significant overlap with the existing Banff classification (adjusted rand index, 0.48). However, the data-driven approach eliminated intermediate and mixed phenotypes and created acute rejection clusters that are each significantly associated with graft failure. Finally, a novel visualization tool presents disease phenotypes and severity in a continuous manner, as a complement to the discrete clusters.

Conclusions: A semisupervised clustering approach for the identification of clinically meaningful novel phenotypes of kidney transplant rejection has been developed and validated. The approach has the potential to offer a more quantitative evaluation of rejection subtypes and severity, especially in situations in which the current histologic categorization is ambiguous.
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http://dx.doi.org/10.1681/ASN.2020101418DOI Listing
March 2021

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

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

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

HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients.

Kidney Int 2021 03 2;99(3):671-685. Epub 2020 Sep 2.

Sorbonne Université, Université Pierre et Marie Curie Paris 06, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1155, Paris, France; Department of Nephrology (Day Hospital), AP-HP, Tenon Hospital, Paris, France. Electronic address:

Recurrence of primary membranous nephropathy after transplantation occurs in up to 44% of patients and is driven by PLA2R antibody. Here, we asked whether genetic determinants could improve risk prediction. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. These were rs9271188 (intergenic between HLA-DRB1 and HLA-DQA1,) and rs9275086 (intergenic between HLA-DQB1 and HLA-DQA2) at the HLA-D locus along with rs6726925 and rs13018963 at the PLA2R1 locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs. Seven SNPs located between HLA-DRB1 and HLA-DQA1 in linkage disequilibrium with rs9271188, and three SNPs in the PLA2R1 region predicted recurrence when presented by the donor, but not when presented by the recipient. The two SNPs in the HLA-D region most strongly associated with recurrence (rs9271705 and rs9271550) were confirmed in the replication cohort. A genetic risk score based on the two best predictors at each locus (rs9271705, rs9271550, rs17830558, and rs3828323) identified a group of patients with high risk of recurrence. Thus, our results suggest that the graft contributes to recurrence of primary membranous nephropathy through the disease susceptibility HLA-D and PLA2R1 SNPs in an autoimmune milieu. Further studies are needed before implementation of genetic testing for these in donor selection.
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http://dx.doi.org/10.1016/j.kint.2020.08.007DOI Listing
March 2021

Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features.

J Neurol Neurosurg Psychiatry 2020 10 10;91(10):1076-1084. Epub 2020 Jul 10.

French National Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hôpital Neurologique, Hospices Civils de Lyon, Bron, France

Objective: Antibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms.

Methods: A cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied.

Results: Cluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/-; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/-; 11/56, 19.6%). LE/- and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (p<0.05). Conversely, DRB1*11:01 association was absent in PNH/+ patients, but only they had malignant thymoma (87.5%), serum antibodies against leucine-rich glioma-inactivated 1 protein (66.7%) and against netrin-1 receptor deleted in colorectal carcinoma (53.8%), and myasthenia gravis (50.0%).

Interpretation: Symptoms' distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis.
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http://dx.doi.org/10.1136/jnnp-2020-323226DOI Listing
October 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

[Relevance of antibodies in hematopoietic stem cell transplantation: Antibodies anti-HLA, anti-platelets, anti-granulocytes, anti-erythrocytes and anti-MICA. Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

Bull Cancer 2020 Dec 12;107(12S):S159-S169. Epub 2020 Jun 12.

EFS Auvergne Rhône Alpes, laboratoire HLA/HPA, 111, rue Elisée-Reclus, 69150 Décines, France. Electronic address:

The presence of allo-antibodies in the serum of a recipient awaiting hematopoietic stem cell transplantation (HSCT) may have an impact on transfusion efficiency and/or donor choice, especially in the absence of an identical sibling donor. Prior to transplantation, donor specific anti-HLA (Human Leukocyte Antigen) antibodies (DSA) have a recognized effect on transplant outcome, correlated with the increasing MFI value and with the ability of such antibody to fix the complement fraction. Anti-platelet antibodies (anti-HLA class I and anti-HPA [Human Platelet Antigen]) are better involved in transfusion inefficiency and can be responsible for refractory status. ABO incompatibilities require a specific treatment of the graft in presence of high titer to avoid hemolytic adverse effects. Investigations of these antibodies should be carried out on a regular basis in order to establish appropriate transfusion recommendation, select an alternative donor when possible or adapt the source of cells. After transplantation, in case of delayed recovery or graft rejection, long term aplasia, persistent mixed chimerism or late release, and after elimination of the main clinical causes, a biological assessment targeted on the different type of antibodies will have to be performed in order to orient towards the cause or the appropriate therapy. Further studies should be carried out to determine the impact of anti-MICA antibodies and recipient specific anti-HLA antibodies, on the outcome of the transplantation.
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http://dx.doi.org/10.1016/j.bulcan.2020.04.015DOI Listing
December 2020

HLA-B leader and survivorship after HLA-mismatched unrelated donor transplantation.

Blood 2020 07;136(3):362-369

Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD; and.

Hematopoietic cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders, but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT, or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B-mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 10 415 patients receiving a transplant between 1988 and 2016 from unrelated donors with one HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Nonrelapse mortality was higher among HLA-DQB1-mismatched MM patients compared with HLA-DQB1-mismatched TT patients (hazard ratio, 1.35; P = .01). Grades III to IV GVHD risk was higher among HLA-DRB1-mismatched MM or MT patients compared with HLA-DRB1-mismatched TT patients (odds ratio, 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's leader genotype.
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http://dx.doi.org/10.1182/blood.2020005743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365916PMC
July 2020

Role of HLA-DP Expression in Graft-Versus-Host Disease After Unrelated Donor Transplantation.

J Clin Oncol 2020 08 1;38(24):2712-2718. Epub 2020 Jun 1.

Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD.

Purpose: The main aim of this study was to evaluate the significance of HLA-DPB1 expression in acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) from HLA-A, -B, -C, -DRB1, -DQB1-matched and -mismatched unrelated donors.

Patients And Methods: Between January 1, 2017, and January 10, 2019, we assessed 19,136 patients who received HCT from an HLA-A, -B, -C, -DRB1, -DQB1-matched or -mismatched unrelated donor performed in Australia, the European Union, Japan, North America, and the United Kingdom between 1988 and 2016. Among transplant recipients with one HLA-DPB1 mismatch, the patient's mismatched HLA-DPB1 allotype was defined as low or high expression. Multivariable regression models were used to assess risks of GVHD associated with high expression relative to low expression HLA-DPB1 mismatches. The effect of increasing numbers of HLA-DPB1 mismatches on clinical outcome was assessed in HLA-mismatched transplant recipients.

Results: In HLA-A, -B, -C, -DRB1,-DQB1-matched transplant recipients, donor mismatching against one high-expression patient HLA-DPB1 increased moderate (odds ratio [OR], 1.36; = .001) and severe acute GVHD (OR, 1.32; = .0016) relative to low-expression patient mismatches, regardless of the expression level of the donor's mismatched HLA-DPB1. Among transplant recipients with one HLA-A, -B, -C, -DRB1, or -DQB1 mismatch, the odds of acute GVHD increased with increasing numbers of HLA-DPB1 mismatches (OR, 1.23 for one; OR, 1.40 for two mismatches relative to zero mismatches for moderate GVHD; OR, 1.19 for one; OR, 1.40 for two mismatches relative to zero for severe GVHD), but not with the level of expression of the patient's mismatched HLA-DPB1 allotype.

Conclusion: The level of expression of patient HLA-DPB1 mismatches informs the risk of GVHD after HLA-A, -B, -C, -DRB1, -DQB1-matched unrelated HCT, and the total number of HLA-DPB1 mismatches informs the risk of GVHD after HLA-mismatched unrelated HCT. Prospective consideration of HLA-DPB1 may help to lower GVHD risks after transplantation.
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http://dx.doi.org/10.1200/JCO.20.00265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430213PMC
August 2020

Predictive value of HLAMatchmaker and PIRCHE-II scores for de novo donor-specific antibody formation after adult and pediatric liver transplantation.

Transpl Immunol 2020 08 16;61:101306. Epub 2020 May 16.

CHU Saint Eloi, Département d'hépatologie et transplantation hépatique, Montpellier, France. Electronic address:

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 <0.05), 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.
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http://dx.doi.org/10.1016/j.trim.2020.101306DOI Listing
August 2020

Eplet incompatibility in pediatric renal transplantation.

Pediatr Transplant 2020 09 10;24(6):e13721. Epub 2020 May 10.

Department of Pediatric Nephrology, Hopital Femme-Mere-Enfant, Lyon, France.

Eplet incompatibility appears to be a better predictor of the de novo appearance of DSA post-Tx than HLA antigen matching in adults. We evaluated the HLA Matchmaker® software (version 2.1) in our pediatric cohort to predict the appearance of DSA post-Tx. We included 70 pediatric patients (26 girls, 10 living donors, mean age 11.2 ± 3.9 years) after a first R-Tx (January 2010-August 2016), without prior immunization, having complete HLA typing (A, B, C, DRB1 and DQB1) and DSA follow-up for at least one year. The mean of HLA and eplet incompatibilities was 4.7 ± 1.3 and 15.5 ± 6.1, respectively, with a correlation coefficient r between these two variables of 0.34 (P < .001). The eplet load was 12.8 ± 5.0 in living donors vs 15.9 ± 6.2 in deceased donors (P = NS), 12.6 ± 6.1 in preemptive R-Tx (n = 14) vs 16.3 ± 5.9 for non-preemptive R-Tx (P = .04). Seven patients (10%) developed DSA during the 3.5 ± 1.2 years post-Tx. The eplet load was 13.7 ± 5.5 for those who developed DSA vs 15.7 ± 6.1 for the others (P = NS). In our single-center series of pediatric R-Tx with good HLA matching and lower eplet load than previously published series, eplet incompatibilities do not predict the development of DSA. The question of the HLA matching requirement and the daily interest of the HLA Matchmaker® software to help select the grafts remain open.
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http://dx.doi.org/10.1111/petr.13721DOI Listing
September 2020

Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus-host disease in conjunction with the CMV status.

Bone Marrow Transplant 2020 07 14;55(7):1367-1378. Epub 2020 Apr 14.

Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Plateforme GENOMAX, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

Graft-versus-host disease (GVHD) and cytomegalovirus (CMV)-related complications are leading causes of mortality after unrelated-donor hematopoietic cell transplantation (UD-HCT). The non-conventional MHC class I gene MICB, alike MICA, encodes a stress-induced polymorphic NKG2D ligand. However, unlike MICA, MICB interacts with the CMV-encoded UL16, which sequestrates MICB intracellularly, leading to immune evasion. Here, we retrospectively analyzed the impact of mismatches in MICB amino acid position 98 (MICB98), a key polymorphic residue involved in UL16 binding, in 943 UD-HCT pairs who were allele-matched at HLA-A, -B, -C, -DRB1, -DQB1 and MICA loci. HLA-DP typing was further available. MICB98 mismatches were significantly associated with an increased incidence of acute (grade II-IV: HR, 1.20; 95% CI, 1.15 to 1.24; P < 0.001; grade III-IV: HR, 2.28; 95% CI, 1.56 to 3.34; P < 0.001) and chronic GVHD (HR, 1.21; 95% CI, 1.10 to 1.33; P < 0.001). MICB98 matching significantly reduced the effect of CMV status on overall mortality from a hazard ratio of 1.77 to 1.16. MICB98 mismatches showed a GVHD-independent association with a higher incidence of CMV infection/reactivation (HR, 1.84; 95% CI, 1.34 to 2.51; P < 0.001). Hence selecting a MICB98-matched donor significantly reduces the GVHD incidence and lowers the impact of CMV status on overall survival.
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http://dx.doi.org/10.1038/s41409-020-0886-5DOI Listing
July 2020

Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies.

J Neurol 2020 Jul 9;267(7):1906-1911. Epub 2020 Mar 9.

French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, 59 Boulevard Pinel, 69677, Bron Cedex, France.

The primary cause of neurological syndromes with antibodies against glutamic acid decarboxylase 65 (GAD65-Ab) is unknown, but genetic predisposition may exist as it is suggested by the co-occurrence in patients and their relatives of other organ-specific autoimmune diseases, notably type 1 diabetes mellitus (T1DM), and by the reports of a few familial cases. We analyzed the human leukocyte antigen (HLA) in 32 unrelated patients and compared them to an ethnically matched sample of 137 healthy controls. Four-digit resolution HLA alleles were imputed from available Genome Wide Association data, and full HLA next-generation sequencing-based typing was also performed. HLA DQA1*05:01-DQB1*02:01-DRB1*03:01 was the most frequent class II haplotype in patients (13/32, 41%). DQB1*02:01 was the only allele found to be significantly more common in patients than in controls (20/137, 15%, corrected p = 0.03, OR 3.96, 95% CI [1.54-10.09]). There was also a trend towards more frequent DQA1*05:01 among patients compared to controls (22/137, 16%; corrected p = 0.05, OR 3.54, 95% CI [1.40-8.91]) and towards a protective effect of DQB1*03:01 (2/32, 6% in patients vs. 42/137, 31% in control group; corrected p = 0.05, OR 0.15, 95% CI [0.02-0.65]). There was no significant demographic or clinical difference between DQ2 and non-DQ2 carriers (p > 0.05). Taken together, these findings suggest a primary DQ effect on GAD65-Ab neurological diseases, partially shared with other systemic organ-specific autoimmune diseases such as T1DM. However, it is likely that other non-HLA loci are involved in the genetic predisposition of GAD65-Ab neurological syndromes.
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http://dx.doi.org/10.1007/s00415-020-09782-8DOI Listing
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

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

Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study.

Lancet Haematol 2020 Jan 25;7(1):e50-e60. Epub 2019 Oct 25.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Background: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT.

Methods: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors.

Findings: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype.

Interpretation: The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials.

Funding: The National Institutes of Health, USA.
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http://dx.doi.org/10.1016/S2352-3026(19)30208-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948919PMC
January 2020

Outcome of Liver Transplant Patients With Preformed Donor-Specific Anti-Human Leukocyte Antigen Antibodies.

Liver Transpl 2020 02 28;26(2):256-267. Epub 2019 Nov 28.

Université Claude Bernard Lyon 1, Villeurbanne, France.

After liver transplantation (LT), the role of preformed donor-specific anti-human leukocyte antigen antibodies (pDSAs) remains incompletely understood. We conducted a retrospective, case-control analysis to determine the impact of pDSAs after LT in 3 French transplant centers (Bordeaux, Lyon, and Toulouse). Among the 1788 LTs performed during the study period, 142 (7.9%) had at least 1 pDSA. The patient survival rate was not different between patients who received an LT with pDSAs and the matched-control group. A liver biopsy was performed 1 year after transplantation in 87 recipients. The metavir fibrosis score did not differ between both groups (1 ± 0.8 versus 0 ± 0.8; P = 0.80). However, undergoing a retransplantation (hazard ratio [HR] = 2.6, 95% confidence interval [CI], 1.02-6.77; P = 0.05) and receiving induction therapy with polyclonal antibodies (HR = 2.5; 95% CI, 1.33-4.74; P = 0.01) were associated with a higher risk of mortality. Nonetheless, high mean fluorescence intensity (MFI) donor-specific antibodies (ie, >10,000 with One Lambda assay or >5000 with Immucor assay) were associated with an increased risk of acute rejection (HR = 2.0; 95% CI, 1.12-3.49; P = 0.02). Acute antibody-mediated rejection was diagnosed in 10 patients: 8 recipients were alive 34 (1-125) months after rejection. The use of polyclonal antibodies or rituximab as an induction therapy did not reduce the risk of acute rejection, but it increased the risk of infectious complications. In conclusion, high MFI pDSAs increase the risk of graft rejection after LT, but they do not reduce medium-term and longterm patient survival. The use of a T or B cell-depleting agent did not reduce the risk of acute rejection.
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http://dx.doi.org/10.1002/lt.25663DOI Listing
February 2020

[Haploidentical hematopoietic stem cell transplant: How to choose the best donor? Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

Bull Cancer 2020 Jan 2;107(1S):S72-S84. Epub 2019 Oct 2.

Université Paris 6 Pierre-et-Marie-Curie, groupe hospitalier Pitié-Salpêtrière, centre d'immunologie et des maladies infectieuses (CIMI-Paris), service d'hématologie clinique, UPMC CR7, CNRS ERL8255, Inserm U1135, 75013 Paris, France. Electronic address:

Haploidentical hematopoietic stem cell transplantation has been growing steadily since 2012. The SFGM-TC has twice published guidelines concerning T-cell repleted haploidentical grafts with high dose cyclophosphamide post-transplantation. The 2013 workshop recommended using the non-myeloablative Baltimore protocol with bone marrow and developed prospective protocols to evaluate these transplantations. The 2015 workshop reported improved results of reduced conditioning regimens in Hodgkin's lymphoma and intensive conditioning in myeloid hemopathies, and a similar outcome with 10/10 HLA matched donor with the same disease-risk score thus raising the question of the qualifier "alternative" for haploidentical transplants. The current work concerns the criteria for selecting the donor. The main criterion remains the absence of anti-HLA antibodies directed against the donor present in the recipient sera (DSA - Donor Specific Antibodies). In case of DSA and in the absence of an alternative donor, desensitization protocols exist. The other criteria are impossible to prioritize: age, sex, CMV, and blood type. The degree of relatedness and the number of HLA incompatibilities do not seem to be a criterion of choice. The 'ideal' donor would be a young man, CMV-matched, without major ABO incompatibility with a marrow transplant. There is insufficient data for the KIR-ligand and NIMA/NIPA mismatch. Peripheral stem cell grafts appear to yield more acute GVHD than bone marrow grafts after intensive conditioning, but with comparable survival rates. Based on the literature review, the comparison of haploidentical with unrelated donors encourages inclusion in existing national protocols randomizing these different donors.
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http://dx.doi.org/10.1016/j.bulcan.2019.07.011DOI Listing
January 2020

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

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

Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome.

J Am Soc Nephrol 2018 07 14;29(7):2000-2013. Epub 2018 Jun 14.

Sorbonne Université, UPMC Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, Paris, France;

Steroid-sensitive nephrotic syndrome (SSNS) is a childhood disease with unclear pathophysiology and genetic architecture. We investigated the genomic basis of SSNS in children recruited in Europe and the biopsy-based North American NEPTUNE cohort. We performed three ancestry-matched, genome-wide association studies (GWAS) in 273 children with NS (Children Cohort Nephrosis and Virus [NEPHROVIR] cohort: 132 European, 56 African, and 85 Maghrebian) followed by independent replication in 112 European children, transethnic meta-analysis, and conditional analysis. GWAS alleles were used to perform glomerular -expression quantitative trait loci studies in 39 children in the NEPTUNE cohort and epidemiologic studies in GWAS and NEPTUNE (97 children) cohorts. Transethnic meta-analysis identified one SSNS-associated single-nucleotide polymorphism (SNP) rs1063348 in the 3' untranslated region of (=9.3×10). Conditional analysis identified two additional independent risk alleles upstream of (rs28366266, =3.7×10) and in the 3' untranslated region of (rs9348883, =9.4×10) within introns of and These three risk alleles were independent of the risk haplotype identified in European patients. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS, with younger age of onset across all cohorts, and with increased odds of complete remission across histologies in NEPTUNE children. rs1063348 associated with decreased glomerular expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1. Transethnic GWAS empowered discovery of three independent risk SNPs for pediatric SSNS. Characterization of these SNPs provide an entry for understanding immune dysregulation in NS and introducing a genomically defined classification.
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http://dx.doi.org/10.1681/ASN.2017111185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050942PMC
July 2018

HLA-DRB3/4/5 mismatches are associated with increased risk of acute GVHD in 10/10 matched unrelated donor hematopoietic cell transplantation.

Am J Hematol 2018 May 4. Epub 2018 May 4.

AP-HP, Hôpital Saint Louis, Service d'hématologie clinique, Paris, France.

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.
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http://dx.doi.org/10.1002/ajh.25133DOI Listing
May 2018

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