Anti-MHC Class II monoclonal antibody, clone EG2699

The 'Immunogenetics of Aging' project is a component introduced in the 14th International HLA and Immunogenetics Workshop (IHIW) and developed further within subsequent workshops. The aim was to determine the relevance of immunogenetic markers, focusing on HLA, cytokine genes, and some innate immunity genes, for successful aging and an increased capacity to reach the extreme limits of life-span. Within the 17th IHIW we applied Next Generation Sequencing methods to refine further HLA associations at allele level in longevity, and to extend our knowledge to additional loci such as HLA-DQA1, HLA-DPB1 and HLA-DPA1. Analysis of relatively small number of healthy elderly and young controls from four populations showed that some HLA class I and class II alleles were significantly positively associated with healthy aging. Additionally we observed statistically significant differences in HLA allele distribution when the analysis was performed separately in elderly females and males compared to sex-matched young controls. Haplotypes, probably associated with better control of viral and malignant diseases were increased in the elderly sample. These preliminary NGS data could confirm our hypotheses that survival and longevity might be associated with selection of HLA alleles and haplotypes conferring disease resistance or susceptibility. Therefore HLA alleles and haplotypes could be informative immunogenetic markers for successful ageing.

The role of HLA amino acid (AA) polymorphism for the outcome of hematopoietic cell transplantation (HCT) is controversial, in particular for HLA class II. Here, we investigated this question in nonpermissive HLA-DPB1 T-cell epitope (TCE) mismatches reflected by numerical functional distance (FD) scores, assignable to all HLA-DPB1 alleles based on the combined impact of 12 polymorphic AAs. We calculated the difference in FD scores (Delta FD) of mismatched HLA-DPB1 alleles in patients and their 10/10 HLA-matched unrelated donors of 379 HCTs performed at our center for acute leukemia or myelodysplastic syndrome. Receiver-operator curve-based stratification into 2 Delta FD subgroups showed a significantly higher percentage of nonpermissive TCE mismatches for Delta FD > 2.665, compared with Delta FD <= 2.665 (88% vs 25%, P < .0001). In multivariate analysis, Delta FD > 2.665 was significantly associated with overall survival (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.05-1.87; P < .021) and event-free survival (HR, 1.39; 95% CI, 1.05-1.82; P < .021), compared with Delta FD <= 2.665. These associations were stronger than those observed for TCE mismatches. There was a marked but not statistically significant increase in the hazards of relapse and nonrelapse mortality in the high Delta FD subgroup, whereas no differences were observed for acute and chronic graft-versus-host disease. Seven nonconservative AA substitutions in peptide-binding positions had a significantly stronger impact on Delta FD compared with 5 others (P = .0025), demonstrating qualitative differences in the relative impact of AA polymorphism in HLA-DPB1. The novel concept of Delta FD sheds new light onto nonpermissive HLA-DPB1 mismatches in unrelated HCT.