Preventing kidney transplant failure by screening for antibodies against human leucocyte antigens followed by optimised immunosuppression: OuTSMART RCT

Design: Investigator-led, prospective, open-labelled marker-based strategy (hybrid) randomised trial. Background: Allografts in 3% of kidney transplant patients fail annually. Development of antibodies against human leucocyte antigens is a validated predictive biomarker of allograft failure. Under immunosuppression is recognised to contribute, but whether increasing immunosuppression can prevent allograft failure in human leucocyte antigen Ab+ patients is unclear. Participants: Renal transplant recipients > 1 year post-transplantation attending 13 United Kingdom transplant clinics, without specific exclusion criteria. Interventions: Regular screening for human leucocyte antigen antibodies followed, in positive patients by interview and tailored optimisation of immunosuppression to tacrolimus, mycophenolate mofetil and prednisolone. Objective: To determine if optimisation of immunosuppression in human leucocyte antigen Ab+ patients can cost-effectively prevent kidney allograft failure. Outcome: Time to graft failure after 43 months follow-up in patients receiving the intervention, compared to controls, managed by standard of care. Costs and quality-adjusted life-years were used in the cost-effectiveness analysis. Randomisation and blinding: Random allocation (1 : 1) to unblinded biomarker-led care or double-blinded standard of care stratified by human leucocyte antigen antibodies status (positive/negative) and in positives, presence of donor-specific antibodies (human leucocyte antigen antibodies against donor human leucocyte antigen) or not (human leucocyte antigen antibodies against non-donor human leucocyte antigen), baseline immunosuppression and transplant centre. Biomaker-led care human leucocyte antigen Ab+ patients received intervention. Human leucocyte antigen Ab-negative patients were screened every 8 months. Recruitment Began September 2013 and for 37 months. The primary endpoint, scheduled for June 2020, was moved to March 2020 because of COVID-19. Numbers randomised: From 5519 screened, 2037 were randomised (1028 biomaker-led care, 1009 to standard of care) including 198 with human leucocyte antigen antibodies against donor human leucocyte antigen (106 biomaker-led care, 92 standard of care) and 818 with human leucocyte antigens antibodies against non-donor human leucocyte antigen (427 biomaker-led care, 391 standard of care). Numbers analysed: Two patients were randomised in error so 2035 were included in the intention-to-treat analysis. Outcome: The trial had 80% power to detect a hazard ratio of 0.49 in biomarker-led care DSA+ group, > 90% power to detect hazard ratio of 0.35 in biomarker-led care non-DSA+ group (with 5% type 1 error). Actual hazard ratios for graft failure in these biomarker-led care groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54 to 1.74), respectively. There was 90% power to demonstrate non-inferiority of overall biomarker-led care group with assumed hazard ratio of 1.4: This was not demonstrated as the upper confidence limit for graft failure exceeded 1.4: (1.02, 95% CI 0.72 to 1.44). The hazard ratio for biopsy-proven rejection in the overall biomarker-led care group was 0.5 [95% CI: 0.27 to 0.94: p = 0.03]. The screening approach was not cost-effective in terms of cost per quality-adjusted life-year. Harms: No significant differences in other secondary endpoints or adverse events. Limitations: Tailored interventions meant optimisation was not possible in some patients. We did not study pathology on protocol transplant biopsies in DSA+ patients. Conclusions: No evidence that optimised immunosuppression in human leucocyte antigen Ab+ patients delays renal transplant failure. Informing patients of their human leucocyte antigen antibodies status appears to reduce graft rejection. Future work: We need a better understanding of the pathophysiology of transplant failure to allow rational development of effective therapies. Trial registration: This trial is registered as EudraCT (2012-004308-36) and ISRCTN (46157828). Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (11/100/34) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 5. See the NIHR Journals Library website for further project information

Fourteen-year experience of human leucocyte antigen typing in cases of disputed parentage in Hong Kong

Seventy-seven cases of disputed parentage were studied using the human leucocyte antigen system over a 14-year period in Hong Kong. Of these, 30 (39.0%) related to the amendment or verification of birth registration details, 20 (26.0%) were for divorce or affiliation proceedings, and 19 (24.7%) were related to overseas resident visa applications. An exclusion of parentage of at least one of the alleged parents was shown in 23 (29.9%) cases; none of the cases related to overseas resident visa applications showed an exclusion. The study illustrates that human leucocyte antigen testing is a very powerful tool in the elucidation of disputed parentage in Hong Kong.published_or_final_versio

Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease

Funded by Wellcome Trust Translational Award SNBTSPeer reviewedPublisher PD

Expression analysis of HLA-E and NKG2A and NKG2C receptors points at a role for natural killer function in ankylosing spondylitis

Background. Ankylosing Spondylitis (AS) is a complex chronic inflammatory disease strongly associated with the majority of HLA-B27 alleles. HLA-E are non-classical MHC class I molecules that specifically interact with the natural killer receptors NKG2A (inhibitory) and NKG2C (activating), and have been recently proposed to be involved in AS pathogenesis. Objectives: To analyze the expression of HLA-E and the CD94/NKG2 pair of receptors in HLA-B27 positive AS patients and healthy controls (HC) bearing the AS-associated, B*2705 and the non-AS-associated, B*2709 allele. Methods: The level of surface expression of HLA-E molecules on CD14 positive peripheral blood mononuclear cell was evaluated in 21 HLA-B*2705 patients with AS, 12 HLA-B*2705 HC, 12 HLA-B*2709 HC and 6 HLA-B27 negative HC, using the monoclonal antibody MEM-E/08 by quantitative cytofluorimetric analysis. The percentage and density of expression of HLA-E ligands NKG2A and NKG2C were also measured on CD3-CD56+ NK cells. Results. HLA-E expression in CD14 positive cells was significantly higher in AS patients (587.0 IQR 424-830) compared to B*2705 HC (389 IQR 251.3-440.5, p=0.0007), B*2709 HC (294.5 IQR 209.5-422, p=0.0004) and HLA-B27 negative HC (380 IQR 197.3-515.0, p=0.01). A higher number of NK cells expressing NKG2A compared to NKG2C was found in all cohort analysed as well as a higher cell surface density. Conclusion: The higher surface level of HLA-E molecules in AS patients compared to HC, concurrently with a prevalent expression of NKG2A, suggests that the crosstalk between these two molecules might play a role in AS pathogenesis accounting for the previously reported association between HLA-E and AS

The performance of different classification criteria sets for spondyloarthritis in the worldwide ASAS-COMOSPA study

Background: In this study, we sought to compare the performance of spondyloarthritis (SpA) classification criteria sets in an international SpA cohort with patients included from five continents around the world. Methods: Data from the (ASAS) COMOrbidities in SPondyloArthritis (ASAS-COMOSPA) study were used. ASAS-COMOSPA is a multinational, cross-sectional study with consecutive patients diagnosed with SpA by rheumatologists worldwide. Patients were classified according to the European Spondyloarthropathy Study Group (ESSG), modified European Spondyloarthropathy Study Group (mESSG), Amor, modified Amor, Assessment of SpondyloArthritis international Society (ASAS) axial Spondyloarthritis (axSpA), ASAS peripheral spondyloarthritis (pSpA) and ClASsification criteria for Psoriatic Arthritis (CASPAR) criteria. Overlap between the classification criteria sets was assessed for patients with and without back pain. Furthermore, patients fulfilling different arms of the ASAS axSpA criteria (imaging arm, clinical arm, both arms) were compared on the presence of SpA features. Results: A total of 3942 patients (5 continents, 26 countries) were included. The mean age was 43.6 years, 65.0% were male, 56.2% were human leucocyte antigen B27-positive and 64.4% had radiographic sacroiliitis (based on modified New York criteria). Of the patients, 85.5% were classified by the ASAS SpA criteria (87.7% ASAS axSpA, 12.3% ASAS pSpA). Fulfilment of the Amor, ESSG and CASPAR criteria was present in 83.3%, 88.4% and 21.6% of patients, respectively. Of the patients with back pain (n = 3227), most were classified by all three of Amor, ESSG and ASAS axSpA criteria (71.4%). Patients fulfilling the imaging arm and the clinical arm of the ASAS axSpA criteria had similar presentations of SpA features. In patients without back pain, overlap between classification criteria sets was seen, although to a lesser extent. Conclusions: Most patients with a clinical diagnosis of axial SpA in the worldwide ASAS-COMOSPA study fulfil several classification criteria sets, and a substantial overlap between different criteria sets is seen, which suggests a high level of credibility of the criteria. Large inter-regional differences in the fulfilment of classification criteria were not found. Patients fulfilling the clinical arm were remarkably similar to patients fulfilling the imaging arm with respect to the presence of most SpA features

Is There Need for a New Hepatitıs B Vaccine Schedule for Children with Celiac Disease?

Background: Celiac disease (CD) is an autoimmune disease characterized by immune-mediated inflammatory damage of the small intestinal mucosa, precipitated by the ingestion of gluten-containing foods. Since human leucocyte antigen DQ2 (HLA-DQ2) is a marker of nonresponsiveness to hepatits B virus (HBV) vaccine, CD may also be associated with this nonresponsiveness

HLA-DRB1 shared epitope genotyping using the revised classification and its association with circulating autoantibodies, acute phase reactants, cytokines and clinical indices of disease activity in a cohort of South African rheumatoid arthritis patients

INTRODUCTION: The revised shared epitope (SE) concept in rheumatoid arthritis (RA) is based on the presence (S) or absence (X) of the SE RAA amino acid motif at positions 72 to 74 of the third hypervariable region of the various human leucocyte antigen (HLA)-DRB1 alleles. The purpose of this study was to investigate SE subtypes on the basis of the American College of Rheumatology 1987 revised criteria for the classification of RA in a cohort of South African RA patients (n = 143) and their association with clinical and circulating biomarkers of disease activity (autoantibodies, acute phase reactants and cytokines). METHODS: Genomic DNA was analysed using high-resolution recombinant sequence-specific oligonucleotide PCR typing of the HLA-DRB1 allele. Subtypes of the SE were classified according to the amino acids at positions 72 to 74 for the RAA sequence, and further sub-divided according to the amino acids at positions 70 and 71, which either contribute to (S2, S3P), or negate (S1, S3D) RA susceptibility. Disease activity was assessed on the basis of (1) Disease Activity Score in 28 joints using C-reactive protein (CRP), (2) rheumatoid factor (RF), (3) CRP and (4) serum amyloid A by nephelometry, anticyclic citrullinated peptide antibodies (aCCP) by an immunofluorometric procedure, and cytokines by multiplex bead array technology. RESULTS: Of the 143 RA patients, 81 (57%) were homozygous (SS) and 50 (35%) were heterozygous (SX) for the SE alleles with significant overexpression of S2 and S3P (respective odds ratios (ORs) 5.3 and 5.8; P < 0.0001), and 12 (8%) were classified as no SE allele (XX). Both the SS and SX groups showed a strong association with aCCP positivity (OR = 10.2 and P = 0.0010, OR = 9.2 and P = 0.0028, respectively) relative to the XX group. Clinical scores and concentrations of the other biomarkers of disease activity (RF, CRP and T helper cell type 1 (Th1), Th2, macrophage and fibroblast cytokines) were also generally higher in the SS group than in the SX and XX groups. CONCLUSIONS: RA susceptibility alleles investigated according to revised criteria for the classification of RA were significantly increased in South African RA patients and strongly associated with aCCP in particular as well as with circulating cytokines and disease severity.The Connective Tissue Diseases Research Fund, University of the Witwatersrandhttp://arthritis-research.com/content/13/5/R16

HLA-B27 as a predictor of effectiveness of treatment with TNF inhibitors in axial spondyloarthritis: data from the Swiss Clinical Quality Management Registry

OBJECTIVE: To explore the impact of the human leucocyte antigen (HLA)-B27 on the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). METHODS: A total of 1109 patients with available HLA-B27 status (831 B27+ patients and 278 B27- patients) fulfilling the Assessment of Spondyloarthritis international Society classification criteria for axSpA from the prospective Swiss Clinical Quality Management Registry initiating a first TNFi were included. Drug retention was investigated with multiple adjusted Cox proportional hazard models with imputation of missing values. Multiple-adjusted logistic regression analyses were used to assess the proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year. RESULTS: B27+ and B27- patients differed with regard to age, sex, BASDAI, C-reactive protein (CRP), body mass index, enthesitis, uveitis, and classification status. After adjustment for potential confounders for the relationship between HLA-B27 and drug effectiveness (sex and family history of spondyloarthritis), a higher risk of drug discontinuation was found in B27- patients (HR 1.53, 95% CI 1.27-1.83). This difference decreased after additional adjustment for parameters which may act as mediators (HR 1.30, 95% CI 1.30-1.55). Male sex and elevated C-reactive protein (CRP) levels were consistently associated with longer retention. Comparable results were obtained for BASDAI50 responses. CONCLUSION: The HLA-B27 genotype is an important predictor of treatment effectiveness. Male sex and CRP seem, however, to better describe variability of response in individual patients. This data may help avoiding potential discrimination of B27- individuals with regard to TNFi initiation. Key Points • HLA-B27 is a predictor of effectiveness of TNF inhibitors in axial spondyloarthritis. • Variability of response in individual patients is better defined by sex and objective markers of disease activity, such as C-reactive protein

HLA class I-redirected anti-tumour CD4+T-cells require a higher TCR binding affinity for optimal activity than CD8+T-cells

CD4+ T helper cells are a valuable component of the immune response towards cancer. Unfortunately, natural tumour-specific CD4+ T-cells occur in low frequency, express relatively low affinity T-cell receptors (TCRs) and show poor reactivity towards cognate antigen. In addition, the lack of human leukocyte antigen (HLA) class II expression on most cancers dictates that these cells are often unable to respond to tumour cells directly. These deficiencies can be overcome by transducing primary CD4+ T-cells with tumour-specific HLA class I-restricted TCRs prior to adoptive transfer. The lack of help from the coreceptor CD8 glycoprotein in CD4+ cells might result in these cells requiring a different optimal TCR binding affinity. Here we compared primary CD4+ and CD8+ T-cells expressing wildtype and a range of affinity-enhanced TCRs specific for the HLA A*0201-restricted NY-ESO-1- and gp100 tumour antigens. Our major findings are: (i) redirected primary CD4+ T-cells expressing TCRs of sufficiently high affinity exhibit a wide range of effector functions, including cytotoxicity, in response to cognate peptide; and, (ii) optimal TCR binding affinity is higher in CD4+ T-cells than CD8+ T-cells. These results indicate that the CD4+ T-cell component of current adoptive therapies using TCRs optimised for CD8+ T-cells is below par and that there is room for substantial improvement. This article is protected by copyright. All rights reserved