HLA-DQ heterodimers in hematopoietic cell transplantation.

HLA-DQ heterodimers increase the susceptibility to autoimmune diseases, but their role in hematopoietic cell transplantation is unknown. We tested the hypothesis that outcome after HLA-matched and HLA-DQ-mismatched hematopoietic cell transplantation is influenced by HLA-DQ heterodimers. Heterodimers were defined in 5164 HLA-matched and 520 HLA-DQ-mismatched patients and their transplant donors according to well-established crystallographic criteria. Group 1 (G1) heterodimers are any DQA1*02/03/04/05/06α paired with any DQB1*02/03/04ß. Group 2 (G2) heterodimers are DQA1*01α paired with any DQB1*05/06ß. Multivariable models identified significantly higher relapse risk in G1G2 and G2G2 compared with G1G1 HLA-matched patients with malignant disease; risk increased with an increasing number of G2 molecules. In HLA-DQ-mismatched transplantation for malignant diseases, matching or mismatching for G2 increased relapse risk. G2 lowered disease-free survival after both HLA-matched and HLA-DQ-mismatched transplantation. A paradigm based on HLA-DQ heterodimers provides a functional definition of the hematopoietic cell transplantation barrier and a means to lower risks for future patients.

Scandiatransplant acceptable mismatch program-10 years with an effective strategy for transplanting highly sensitized patients.

In March 2009, the Scandiatransplant acceptable mismatch program (STAMP) was introduced as a strategy toward improving kidney allocation to highly sensitized patients. Patients with a transplantability score ≤ 2% are potential candidates for the program. Samples are analyzed and acceptable antigens (HLA-A, B, C, DRB1, DRB3/4/5, DQB1, DQA1, DPB1, DPA1) are defined by the local tissue typing laboratory and finally evaluated by a steering committee. In the matching algorithm, patients have the highest priority when the donor's antigens are all among the recipient's own or acceptable HLA antigens. In the period from 2009 to 2020, we have transplanted 278 highly sensitized kidney patients through the program. The graft survival of the STAMP patients was compared with 9002 deceased donor kidney-transplanted patients, transplanted in the same time period. The 10-year graft survival was 73.4% (95% CI: 60.3-90.0) for STAMP and 82.9% (95% CI: 81.6-84.3) for the reference group. (p = .2). In conclusion, the 10-year allograft survival demonstrates that the STAMP allocation algorithm is immunological safe. The program is continuously monitored and evaluated, and the introduction of matching for all HLA loci is a huge improvement to the program and demonstrate technical adaptability as well as clinical flexibility in a de-centralized organization.

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

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.

IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.

BACKGROUND: Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab')2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1-2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor. METHODS: We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound. RESULTS: Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred. CONCLUSIONS: IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).

Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients.

Safety, immunogenicity, pharmacokinetics, and efficacy of the IgG-degrading enzyme of Streptococcus pyogenes (IdeS [imlifidase]) were assessed in a single-center, open-label ascending-dose study in highly sensitized patients with chronic kidney disease. Eight patients with cytotoxic PRAs (median cytotoxic PRAs of 64%) at enrollment received 1 or 2 intravenous infusions of IdeS on consecutive days (0.12 mg/kg body weight ×2 [n = 3]; 0.25 mg/kg ×1 [n = 3], or 0.25 mg/kg ×2 [n = 2]). IgG degradation was observed in all subjects after IdeS treatment, with <1% plasma IgG remaining within 48 hours and remaining low up to 7 days. Mean fluorescence intensity values of HLA class I and II reactivity were substantially reduced in all patients, and C1q binding to anti-HLA was abolished. IdeS also cleaved the IgG-type B cell receptor on CD19+ memory B cells. Anti-IdeS antibodies developed 1 week after treatment, peaking at 2 weeks. A few hours after the second IdeS infusion, 1 patient received a deceased donor kidney offer. At enrollment, the patient had a positive serum crossmatch (HLA-B7), detected by complement-dependent cytotoxicity, flow cytometry, and multiplex bead assays. After IdeS infusion (0.12 mg/kg ×2) and when the HLA-incompatible donor (HLA-B7+ ) kidney was offered, the HLA antibody profile was negative. The kidney was transplanted successfully.

Suitability Criteria for Adult Related Donors: A Consensus Statement from the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues.

The number of allogeneic hematopoietic stem cell (HSC) transplants performed globally each year continues to increase. Advances in HLA typing, better supportive care, and administration of reduced-intensity conditioning regimens allow treatment of older patients with older sibling donors. Pretransplant donor assessment and testing are very important processes affecting the quality and safety of donation. For unrelated HSC donors detailed recommendations for health assessment have been published, allowing donation only if they are unrestrictedly healthy. Eligibility criteria for related donors are less strict and vary significantly between centers. In situations where a family donor does not meet the suitability criteria for unrelated donors, involved physicians often struggle with the decision whether the matched relative is suitable for donation or not. On behalf of the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues, we intended to develop a consensus document with recommendations for donor workup and final clearance of family donors who would not be able to serve as unrelated donors because of their age or pre-existing diseases. This article covers different topics intending to support decision-making, with the goal of minimizing medical risk to the donor and protection of the recipient from transmissible diseases.

High metal ion levels after use of the ASR™ device correlate with development of pseudotumors and T cell activation.

BACKGROUND: Pseudotumors and immunologic alterations are reported in patients with elevated metal ion levels after resurfacing arthroplasty of the hip. A direct association of increased cobalt and chromium concentrations with the development of pseudotumors has not been established. QUESTIONS/PURPOSES: We hypothesized that (1) patients with higher blood cobalt and chromium concentrations are more likely to have pseudotumors develop, (2) elevated cobalt and chromium concentrations correlate with increased activation of defined T cell populations, and (3) elevated metal ion levels, small implant size, cup inclination angle, and patient age are risk factors for the development of pseudotumors. METHODS: A single-surgeon cohort of 78 patients with 84 Articular Surface Replacement(®) implants was retrospectively investigated. Between 2006 and 2010, we performed 84 THAs using the Articular Surface Replacement(®) implant; this represented 2% (84/4950) of all primary hip replacements performed during that period. Of the procedures performed using this implant, we screened 77 patients (99%) at a mean of 43 months after surgery (range, 24-60 months). Seventy-one patients were investigated using ultrasound scanning, and cobalt and chromium concentrations in whole blood were determined by high-resolution inductively coupled plasma mass spectrometry. Differential analysis of lymphocyte subsets was performed by flow cytometry in 53 patients. Results of immunologic analyses were investigated separately for patients with and without pseudotumors. Pseudotumors were found in 25 hips (35%) and were more common in women than in men (p = 0.02). Multivariable regression analysis was performed to identify risk factors for the development of pseudotumors. RESULTS: Cobalt and chromium concentrations were greater in patients with pseudotumors than in those without (cobalt, median 8.3 versus median 1.0 µg/L, p < 0.001; chromium, median 5.9 versus median 1.3 µg/L, p < 0.001). The percentage of HLA-DR(+)CD4(+) T cells was greater in patients with pseudotumors than in those without (p = 0.03), and the proportion of this lymphocyte subtype was positively correlated with cobalt concentrations (r = 0.3, p = 0.02). Multivariable regression analysis indicated that increasing cobalt levels were associated with the development of pseudotumors (p < 0.001), and that patients with larger implants were less likely to have them develop (p = 0.04); age and cup inclination were not risk factors. CONCLUSIONS: We found a distinct association of elevated metal ion concentrations with the presence of pseudotumors and a correlation of increased cobalt concentrations with the proportion of activated T helper/regulator cells. Thus, the development of soft tissue masses after metal-on-metal arthroplasty could be accompanied by activation of T cells, indicating that this complication may be partly immunologically mediated. Further investigations of immunologic parameters in larger cohorts of patients with metal-on-metal arthroplasties are warranted. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

Increased risk of persistent neuropathic pain after traumatic nerve injury and surgery for carriers of a human leukocyte antigen haplotype.

ABSTRACT: It is not known why some patients develop persistent pain after nerve trauma while others do not. Among multiple risk factors for the development of persistent posttrauma and postsurgical pain, a neuropathic mechanism due to iatrogenic nerve lesion has been proposed as the major cause of these conditions. Because there is some evidence that the human leukocyte antigen (HLA) system plays a role in persistent postsurgical pain, this study aimed to identify the genetic risk factors, specifically among HLA loci, associated with chronic neuropathic pain after traumatic nerve injuries and surgery in the upper extremities. Blood samples were taken to investigate the contribution of HLA alleles (ie, HLA-A, HLA-B, HLA-DRB1, HLA-DQB1, and HLA-DPB1) in a group of patients with persistent neuropathic pain (n = 70) and a group of patients with neuropathy without pain (n = 61). All subjects had intraoperatively verified nerve damage in the upper extremity. They underwent bedside clinical neurological examination to identify the neuropathic pain component according to the present grading system of neuropathic pain. Statistical analyses on the allele and haplotype were conducted using the BIGDAWG package. We found that the HLA haplotype A*02:01-B*15:01-C*03:04-DRB1*04:01-DQB1*03:02 was associated with an increased risk of developing persistent neuropathic pain in the upper extremity (OR = 9.31 [95% CI 1.28-406.45], P < 0.05). No significant associations were found on an allele level when correcting for multiple testing. Further studies are needed to investigate whether this association is on a haplotypic level or if certain alleles may be causing the association.

Scandiatransplant Exchange Program (STEP): Development and Results From an International Kidney Exchange Program.

Background: Kidney transplant candidates may be incompatible with their intended living donors because of the presence of antibodies against HLA and/or ABO. To increase the possibility of finding an acceptable kidney donor for these patients, the Scandiatransplant Exchange Program (STEP) program within Scandiatransplant was launched in 2019. Methods: This is a retrospective review of our experiences from the first 4 y of the STEP program, including details about the match runs, performed transplantations, and recipient outcomes within the program. Results: During 2019-2022, 11 match runs and 4 reruns were performed. In total, 114 pairs and 6 anonymous donors participated in these match runs. Fifty-one pairs (45%) participated in 1 match run, 31 pairs (27%) participated in 2 match runs, and 32 pairs (29%) participated in ≥3 match runs. Seventy-two individuals (63%) participated because of HLA incompatibility, 19 (17%) because of ABO incompatibility, and 7 (6%) because of both HLA and ABO incompatibility.Forty percent of the patients enrolled in the program underwent transplantation. In total, 49 transplantations have so far been performed within the program, and 46 (94%) of the recipients had a functioning kidney graft at follow-up in February 2023. Conclusions: The STEP program offers sensitized patients an enlarged pool of living donors and a chance of a compatible international living donor, resulting in an increased number of total transplantations. Currently, STEP is one of the largest transnational kidney exchange programs and has improved the situation for patients waiting for kidney transplantation in Scandiatransplant.

Donor-derived urologic cancers after renal transplantation: A retrospective non-randomized scientific analysis.

BACKGROUND: Malignancies in the urinary tract and the kidney graft are quite common after kidney transplantation. In some selected cases tumours develop from donor-derived tissue. OBJECTIVES: We hypothesised that there is a clinical value to investigate donor/recipient origin in urologic malignancies in renal transplant recipients. METHODS: In this retrospective study, including patients transplanted between the years 1969 and 2014 at Uppsala University Hospital, Sweden, 11 patients with malignancies in urinary tract and 4 patients with malignancies in kidney transplants were investigated. Donor/recipient origin of tumour tissue was analysed by polymerase chain reaction (PCR) of human leucocyte antigen (HLA) genotypes or by fluorescence in situ hybridization (FISH analysis) of sex chromosomes. HLA genotype and sex chromosomes of the tumour were compared to the known HLA genotype and sex chromosomes of recipient and donor. RESULTS: Three of ten cancers in the urinary tract and three of four cancers in the kidney transplants were donor-derived. CONCLUSIONS: We suggest that urologic malignancies in renal transplant recipients can be investigated for transplant origin. In addition to conventional therapy the allograft immune response against these tumours can be valuable to treat donor-derived cancers.

Early developing celiac disease in children with cerebral palsy.

OBJECTIVES: We have reported on increased levels of antibodies against gliadin and/or transglutaminase 2 (TG2) in children with cerebral palsy (CP) but without having increased prevalence of celiac disease (CD). The aim of the present study was to evaluate whether these children have mucosal signs of early developing CD, human leukocyte antigen (HLA)-DQ2/DQ8, and antibodies against deamidated gliadin peptides (DGP). PATIENTS AND METHODS: Stored blood samples from 16 children with CP were analyzed regarding HLA-DQ2/DQ8 and anti-DGP antibodies. HLA-DQ2/DQ8 were analyzed by polymerase chain reaction sequence-specific oligonucleotide probes. Anti-DGP antibodies were analyzed with enzyme-linked immunosorbent assay. Small-bowel biopsies from 15 of these children were available for immunohistochemistry regarding IgA colocalized with TG2, densities of α/ß+ and γ/δ+ intraepithelial lymphocytes. RESULTS: Mucosal immunoglobulin A (IgA) deposits colocalized with TG2 were found in the small-bowel biopsy from 1 patient with serum IgA-class anti-TG2 antibodies, HLA-DQ2, and gastrointestinal complaints. Another 2 children had slightly increased numbers of mucosal α/ß+ and/or γ/δ+ intraepithelial lymphocytes. In total, 10 of 16 children were HLA-DQ2 and/or DQ8-positive. Anti-DGP antibodies were detected in sera from 4 of 16 children. CONCLUSIONS: In the present study, 1 child with CP had IgA colocalizing with TG2 in the small-bowel mucosa, suggesting CD at an early stage. Although the majority of children with CP and elevated levels of CD-related seromarkers are HLA-DQ2 and/or DQ8-positive, they have neither classical nor early developing CD.

Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations.

Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein sequence level. Consequently, genetic variants in noncoding and untranslated HLA gene segments have not been fully explored but could also be important determinants for MG. To gain further insight into the role of HLA in MG, we applied next-generation sequencing to analyze sequence variation at eleven HLA genes in early-onset (EO) and late-onset (LO) non-thymomatous MG patients positive for the acetylcholine receptor (AChR) antibodies and ethnically matched controls from Italy, Norway, and Sweden. For all three populations, alleles and haplotype blocks present on the ancestral haplotype AH8.1 were associated with risk in AChR-EOMG patients. HLA-B*08:01:01:01 was the dominant risk allele in Italians (OR = 3.28, P = 1.83E-05), Norwegians (OR = 3.52, P = 4.41E-16), and in Swedes HLA-B*08:01 was the primary risk allele (OR = 4.24, P <2.2E-16). Protective alleles and haplotype blocks were identified on the HLA-DRB7, and HLA-DRB13.1 class II haplotypes in Italians and Norwegians, whereas in Swedes HLA-DRB7 exhibited the main protective effect. For AChR-LOMG patients, the HLA-DRB15.1 haplotype and associated alleles were significantly associated with susceptibility in all groups. The HLA-DR13-HLA-DR-HLA-DQ haplotype was associated with protection in all AChR-LOMG groups. This study has confirmed and extended previous findings that the immunogenetic predisposition profiles for EOMG and LOMG are distinct. In addition, the results are consistent with a role for non-coding HLA genetic variants in the pathogenesis of MG.

Imlifidase Desensitization in Crossmatch-positive, Highly Sensitized Kidney Transplant Recipients: Results of an International Phase 2 Trial (Highdes).

BACKGROUND: Highly HLA sensitized patients have limited access to life-saving kidney transplantation because of a paucity of immunologically suitable donors. Imlifidase is a cysteine protease that cleaves IgG leading to a rapid decrease in antibody level and inhibition of IgG-mediated injury. This study investigates the efficacy and safety of imlifidase in converting a positive crossmatch test to negative, allowing highly sensitized patients to be transplanted with a living or deceased donor kidney. METHODS: This open-label, single-arm, phase 2 trial conducted at 5 transplant centers, evaluated the ability of imlifidase to create a negative crossmatch test within 24 h. Secondary endpoints included postimlifidase donor-specific antibody levels compared with predose levels, renal function, and pharmacokinetic/pharmacodynamic profiles. Safety endpoints included adverse events and immunogenicity profile. RESULTS: Of the transplanted patients, 89.5% demonstrated conversion of baseline positive crossmatch to negative within 24 h after imlifidase treatment. Donor-specific antibodies most often rebounded 3-14 d postimlifidase dose, with substantial interpatient variability. Patient survival was 100% with graft survival of 88.9% at 6 mo. With this, 38.9% had early biopsy proven antibody-mediated rejection with onset 2-19 d posttransplantation. Serum IgG levels began to normalize after ~3-7 d posttransplantation. Antidrug antibody levels were consistent with previous studies. Seven adverse events in 6 patients were classified as possibly or probably related to treatment and were mild-moderate in severity. CONCLUSIONS: Imlifidase was well tolerated, converted positive crossmatches to negative, and enabled patients with a median calculated panel-reactive antibody of 99.83% to undergo kidney transplantation resulting in good kidney function and graft survival at 6 mo.

Safety of Use of Tantalum in Total Hip Arthroplasty.

BACKGROUND: Tantalum implants have been used in >500,000 orthopaedic patients. Although the risks of metallosis and aseptic lymphocyte-dominated vasculitis-associated lesions (ALVAL) after total hip arthroplasty (THA) are being debated, we are not aware of any studies investigating the liberation of tantalum ions and their potential effects on the immune system. We evaluated whether tantalum concentrations are elevated after THA with acetabular tantalum implants and assessed potential alterations in T-cell subpopulations. METHODS: After a mean follow-up of 4 years (range, 0.5 to 8.9 years) of 144 patients who had undergone THA, blood samples were analyzed regarding blood tantalum concentrations, total white blood-cell counts, and lymphocyte subsets in 3 groups of patients: those treated with non-tantalum primary THA ("primary non-tantalum," n = 30), those treated with primary THA with a tantalum cup ("primary tantalum," n = 30), and those who underwent revision surgery with a tantalum shell ("revision tantalum," n = 84). Blood donors served as controls for immunological parameters (n = 59). Correlations between tantalum concentrations and human leukocyte antigen (HLA)-DR T cells were calculated, radiographic signs of implant loosening were assessed, and the Harris hip score (HHS) was used to evaluate hip function. RESULTS: The median tantalum concentration was similar to the detection limit both in the primary non-tantalum group (0.05 µg/L, 95% confidence interval [CI] = 0.05 to 0.05 µg/L) and in the primary tantalum group (0.051 µg/L, 95% CI = 0.050 to 0.055 µg/L), and it was 0.091 µg/L (95% CI = 0.083 to 0.112 µg/L) in the revision tantalum group (p < 0.0001 in the group-wise comparison with both primary non-tantalum and primary tantalum). We found a weak negative correlation of higher tantalum concentration with the concentration of HLA-DR/CD8 T cells (r = -0.22, 95% CI = -0.35 to -0.05, p = 0.01) but no correlation of tantalum concentration with the concentration of HLA-DR/CD4 T cells (r = -0.11, 95% CI = -0.27 to 0.06, p = 0.24). The values for all lymphocyte subgroups were within normal ranges. No implants were deemed loose. The median HHS was good to excellent. CONCLUSIONS: Exposure to stable tantalum cups is associated with low blood concentrations of tantalum. Signs of T-cell activation typical of ALVAL seem to be lacking. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

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

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.

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

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; P = .001) and severe acute GVHD (OR, 1.32; P = .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.

Common, intermediate and well-documented HLA alleles in world populations: CIWD version 3.0.0.

A catalog of common, intermediate and well-documented (CIWD) HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQB1 and -DPB1 alleles has been compiled from over 8 million individuals using data from 20 unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two-field) and G group assignments are divided into one of four frequency categories: common (≥1 in 10 000), intermediate (≥1 in 100 000), well-documented (≥5 occurrences) or not-CIWD. Overall 26% of alleles in IPD-IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two-field catalog includes 18% (n = 545) common, 17% (n = 513) intermediate, and 65% (n = 1997) well-documented alleles. Full-field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole.

Identification of the novel HLA-B*08:181 allele in a volunteer donor for hematopoietic stem cells.

HLA-B*08:181 differs from HLA-B*08:01:01:01 in codon 94, 95, 97 and 99 of exon 3.

A new allele found in a volunteer hematopoietic stem cell donor: HLA-B*15:465.

HLA-B*15:465 differs from HLA-B*15:01:01:01 in codon 336 of exon 7.