scholarly journals Recombinant human monoclonal HLA antibodies of different IgG subclasses recognising the same epitope: Excellent tools to study differential effects of donor‐specific antibodies

HLA ◽  
2019 ◽  
Vol 94 (5) ◽  
pp. 415-424 ◽  
Author(s):  
Cynthia S. M. Kramer ◽  
Marry E. I. Franke‐van Dijk ◽  
Ashley J. Priddey ◽  
Tamás Pongrácz ◽  
Elena Gnudi ◽  
...  
Keyword(s):  
Igg Subclasses ◽  
Hla Antibodies ◽  
Specific Antibodies ◽  
Differential Effects ◽  
Donor Specific Antibodies

CRISPR/Cas9-Engineered HLA-Deleted Glomerular Endothelial Cells as a Tool to Predict Pathogenic Non-HLA Antibodies in Kidney Transplant Recipients

2021 ◽  
Vol 32 (12) ◽  
pp. 3231-3251
Author(s):  
Baptiste Lamarthée ◽  
Carole Burger ◽  
Charlotte Leclaire ◽  
Emilie Lebraud ◽  
Aniela Zablocki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Kidney Transplant ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Hla Antibodies ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Biopsy Specimens ◽  
Glomerular Endothelial Cells ◽  
Donor Specific Antibodies

BackgroundAfter kidney transplantation, donor-specific antibodies against human leukocyte antigen donor-specific antibodies (HLA-DSAs) drive antibody-mediated rejection (ABMR) and are associated with poor transplant outcomes. However, ABMR histology (ABMRh) is increasingly reported in kidney transplant recipients (KTRs) without HLA-DSAs, highlighting the emerging role of non-HLA antibodies (Abs).MethodsW e designed a non-HLA Ab detection immunoassay (NHADIA) using HLA class I and II–deficient glomerular endothelial cells (CiGEnCΔHLA) that had been previously generated through CRISPR/Cas9-induced B2M and CIITA gene disruption. Flow cytometry assessed the reactivity to non-HLA antigens of pretransplantation serum samples from 389 consecutive KTRs. The intensity of the signal observed with the NHADIA was associated with post-transplant graft histology assessed in 951 adequate biopsy specimens.ResultsW e sequentially applied CRISPR/Cas9 to delete the B2M and CIITA genes to obtain a CiGEnCΔHLA clone. CiGEnCΔHLA cells remained indistinguishable from the parental cell line, CiGEnC, in terms of morphology and phenotype. Previous transplantation was the main determinant of the pretransplantation NHADIA result (P<0.001). Stratification of 3-month allograft biopsy specimens (n=298) according to pretransplantation NHADIA tertiles demonstrated that higher levels of non-HLA Abs positively correlated with increased glomerulitis (P=0.002), microvascular inflammation (P=0.003), and ABMRh (P=0.03). A pretransplantation NHADIA threshold of 1.87 strongly discriminated the KTRs with the highest risk of ABMRh (P=0.005, log-rank test). A multivariate Cox model confirmed that NHADIA status and HLA-DSAs were independent, yet synergistic, predictors of ABMRh.ConclusionThe NHADIA identifies non-HLA Abs and strongly predicts graft endothelial injury independent of HLA-DSAs.

scholarly journals Donor-Specific Antibodies in Kidney Transplant Recipients

2017 ◽  
Vol 13 (1) ◽  
pp. 182-192 ◽  
Author(s):  
Rubin Zhang
Keyword(s):  
Kidney Transplant ◽  
De Novo ◽  
Binding Capacity ◽  
Graft Loss ◽  
Igg Subclasses ◽  
Kidney Transplant Recipients ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Donor Specific Antibodies ◽  
Transplant Glomerulopathy

Donor-specific antibodies have become an established biomarker predicting antibody-mediated rejection. Antibody-mediated rejection is the leading cause of graft loss after kidney transplant. There are several phenotypes of antibody-mediated rejection along post-transplant course that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity. Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection. De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy. The pathogeneses of antibody-mediated rejection include not only complement-dependent cytotoxicity, but also complement-independent pathways of antibody-mediated cellular cytotoxicity and direct endothelial activation and proliferation. The novel assay for complement binding capacity has improved our ability to predict antibody-mediated rejection phenotypes. C1q binding donor-specific antibodies are closely associated with acute antibody-mediated rejection, more severe graft injuries, and early graft failure, whereas C1q nonbinding donor-specific antibodies correlate with subclinical or chronic antibody-mediated rejection and late graft loss. IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor. Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy. Our in-depth knowledge of complex characteristics of donor-specific antibodies can stratify the patient’s immunologic risk, can predict distinct phenotypes of antibody-mediated rejection, and hopefully, will guide our clinical practice to improve the transplant outcomes.

scholarly journals HLA class II donor specific antibodies are associated with graft cirrhosis after liver transplant independent of the mean fluorescence intensity level

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Katharina Willuweit ◽  
Alexandra Frey ◽  
Lisa Bieniek ◽  
Andreas Heinold ◽  
Matthias Büchter ◽  
...  
Keyword(s):  
Patient Survival ◽  
Hla Class I ◽  
Class Ii ◽  
Hla Class Ii ◽  
Intensity Level ◽  
Hla Antibodies ◽  
Specific Antibodies ◽  
Luminex Assay ◽  
The Mean ◽  
Donor Specific Antibodies

Abstract Background The importance of donor-specific antibodies (DSA) after liver transplantation (LT) for graft and patient survival is an ongoing controversy. So far it has not been elucidated when and in how far DSA are harmful for graft and patient survival. Therefore, we had the aim to investigate the association of DSA with complications after LT. Methods Data of 430 LT recipients were collected and statistically analyzed. Detection of HLA antibodies (Ab) was performed by Luminex assay. Results DSA were detected in 81 patients (18.8%). These were mainly HLA class II Ab (81.5%). HLA class II Ab show a higher MFI (median: 5.300) compared to HLA class I Ab (median: 2.300). There is no association between MFI levels and development of complications after LT. However, cirrhosis occurred significantly more often in DSA positive patients (18%) than in patients without detectable DSA (9%, P = 0.027). All DSA positive patients with cirrhosis of the graft showed HLA class II antibodies (OR: 3.028; 95% CI: 1.51–6.075; P = 0.002). Conclusion Occurrence of HLA class II DSA after LT is associated with graft cirrhosis and may indicate a higher risk to develop graft damage independent on MFI and requires an individualized risk management.

Impact on mid-term kidney graft outcomes of pretransplant anti-HLA antibodies detected by solid-phase assays: Do donor-specific antibodies tell the whole story?

2017 ◽  
Vol 78 (9) ◽  
pp. 526-533 ◽  
Author(s):  
Jorge Malheiro ◽  
Sandra Tafulo ◽  
Leonídio Dias ◽  
La Salete Martins ◽  
Isabel Fonseca ◽  
...  
Keyword(s):  
Solid Phase ◽  
Kidney Graft ◽  
Hla Antibodies ◽  
Specific Antibodies ◽  
Donor Specific Antibodies

scholarly journals Not All Antibodies Are Created Equal: Factors That Influence Antibody Mediated Rejection

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Carrie L. Butler ◽  
Nicole M. Valenzuela ◽  
Kimberly A. Thomas ◽  
Elaine F. Reed
Keyword(s):  
Hla Antigens ◽  
Clinical Context ◽  
Hla Antibodies ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Single Antigen ◽  
Specific Antibody Production ◽  
Subclinical Rejection ◽  
Donor Specific Antibodies ◽  
New Evidence

Consistent with Dr. Paul Terasaki’s “humoral theory of rejection” numerous studies have shown that HLA antibodies can cause acute and chronic antibody mediated rejection (AMR) and decreased graft survival. New evidence also supports a role for antibodies to non-HLA antigens in AMR and allograft injury. Despite the remarkable efforts by leaders in the field who pioneered single antigen bead technology for detection of donor specific antibodies, a considerable amount of work is still needed to better define the antibody attributes that are associated with AMR pathology. This review highlights what is currently known about the clinical context of pre and posttransplant antibodies, antibody characteristics that influence AMR, and the paths after donor specific antibody production (no rejection, subclinical rejection, and clinical dysfunction with AMR).

scholarly journals Apheresis Efficacy and Tolerance in the Setting of HLA-Incompatible Kidney Transplantation

2021 ◽  
Vol 10 (6) ◽  
pp. 1316
Author(s):  
Johan Noble ◽  
Antoine Metzger ◽  
Hamza Naciri Bennani ◽  
Melanie Daligault ◽  
Dominique Masson ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Adverse Events ◽  
Mean Fluorescence Intensity ◽  
Single Center ◽  
Hla Antibodies ◽  
Specific Antibodies ◽  
Double Filtration Plasmapheresis ◽  
Donor Specific Antibodies ◽  
Double Filtration ◽  
Hla Incompatible

Nearly 18% of patients on a waiting list for kidney transplantation (KT) are highly sensitized, which make access to KT more difficult. We assessed the efficacy and tolerance of different techniques (plasma exchanges [PE], double-filtration plasmapheresis [DFPP], and immunoadsorption [IA]) to remove donor specific antibodies (DSA) in the setting of HLA-incompatible (HLAi) KT. All patients that underwent apheresis for HLAi KT within a single center were included. Intra-session and inter-session Mean Fluorescence Intensity (MFI) decrease in DSA, clinical and biological tolerances were assessed. A total of 881 sessions were performed for 45 patients: 107 DFPP, 54 PE, 720 IA. The procedures led to HLAi KT in 39 patients (87%) after 29 (15–51) days. A higher volume of treated plasma was associated with a greater decrease of inter-session class I and II DSA (p = 0.04, p = 0.02). IA, PE, and a lower maximal DSA MFI were associated with a greater decrease in intra-session class II DSA (p < 0.01). Safety was good: severe adverse events occurred in 17 sessions (1.9%), more frequently with DFPP (6.5%) p < 0.01. Hypotension occurred in 154 sessions (17.5%), more frequently with DFPP (p < 0.01). Apheresis is well tolerated (IA and PE > DFPP) and effective at removing HLA antibodies and allows HLAi KT for sensitized patients.

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