Human leukocyte antigen (HLA)-A, -C, -B, -DRB1 and -DQB1 alleles were typed in 200 Polish healthy volunteers recruited for stem cell donor registry, using sequence-specific primer (SSP) and direct sequencing-based methods. Enhanced Bayesian approach of expectation maximization algorithm provided by phase platform was used for extended HLA haplotype inferences. The numbers of identified alleles (four-digit resolution) were 23, 23, 44, 27 and 18 alleles in HLA-A, -C, -B, -DRB1 and -DQB1 loci, respectively, of both northern and southern European frequency characteristics. The most frequent extended haplotypes were Cw*0701-B*0801-DRB1*0301-DQB1*0201 and Cw*0702-B*0702-DRB1*1501-DQB1*0602, found in 25 and 23 copies, respectively, in 400 tested chromosomes. The extended haplotype found in the Polish population with higher frequency than in other European population was A*2501-Cw*1203-B*1801-DRB1*1501-DQB1*0602 (six copies) and especially its class I fragment (14 copies). The neighbour-joining and correspondence analyses showed Central and northern European genetic affinities of Polish population. In most cases, the observed European allele and haplotype gradients display smooth topography around Polish population. Poles along with Western Slavs have their specific contribution in the demographic history of Europe. Our results will intensify the use of population data in stem cell donor search and can potentially improve current algorithms, facilitating selection of acceptable donors for patients in need of stem cell transplant.

Some cancers treated with allogeneic hematopoietic stem cell transplantation (HSCT) are sensitive to natural killer cell (NK) reactivity. NK function depends on activating and inhibitory receptors and is modified by NK education/licensing effect and mediated by coexpression of inhibitory killer-cell immunoglobulin-like receptor (KIR) and its corresponding HLA I ligand. We assessed activating KIR (aKIR)-based HLA I-dependent education capacity in donor NKs in 285 patients with hematological malignancies after HSCT from unrelated donors. We found significantly adverse progression-free survival (PFS) and time to progression (TTP) in patients who received transplant from donors with NKs educated by C1:KIR2DS2/3, C2:KIR2DS1, or Bw4:KIR3DS1 pairs (for PFS: hazard ratio [HR], 1.70; P = .0020, Pcorr = .0039; HR, 1.54; P = .020, Pcorr = .039; HR, 1.51; P = .020, Pcorr = .040; and for TTP: HR, 1.82; P = .049, Pcorr = .096; HR, 1.72; P = .096, Pcorr = .18; and HR, 1.65; P = .11, Pcorr = .20, respectively). Reduced PFS and TTP were significantly dependent on the number of aKIR-based education systems in donors (HR, 1.36; P = .00031, Pcorr = .00062; and HR, 1.43; P = .019, Pcorr = .038). Furthermore, the PFS and TTP were strongly adverse in patients with missing HLA ligand cognate with educating aKIR-HLA pair in donor (HR, 3.25; P = .00022, Pcorr = .00045; and HR, 3.82; P = .027, Pcorr = .054). Together, these data suggest important qualitative and quantitative role of donor NK education via aKIR-cognate HLA ligand pairs in the outcome of HSCT. Avoiding the selection of transplant donors with high numbers of aKIR-HLA-based education systems, especially for recipients with missing cognate ligand, is advisable.

Previous reports have implicated the tumor necrosis factor (TNF-308) locus to non-Hodgkin's lymphoma (NHL) outcome. The purpose of the study was to examine other chromosome components of the HLA 8.1 ancestral haplotype (AH) and their relation to the clinical course of NHL. HLA class I, II, TNF-308, and lymphotoxin alpha (LTA+252) alleles were analyzed in 154 newly diagnosed NHL patients. Three locus haplotypes were inferred from the unphased genotypes by a Bayesian implementation of the expectation maximization (EM) algorithm using the PHASE 2.1 program. TNF-308A was the only allele associated with fever, poor performance status, elevated beta2-microglobulin, TNF and its p75 receptor plasma levels. Although TNF-308A was in strong linkage disequilibrium with the remaining alleles of 8.1 AH, only HLA-A*01 and HLA-B*08 showed association with prognostic variables. A part of 8.1 AH (A*01-B*08-TNF-308A) was predictive for shorter freedom from progression and overall survival (RR=2.47, P=0.041; RR=3.15; P=0.0049), an association that was stronger than TNF-308A alone and independent from International Prognostic Index (RR=1.55, P<0.001; RR=2.36; P<0.0001). A*01-B*08-TNF-308A fragment of 8.1 AH remained an independent predictive factor in a multivariate model. We conclude that 8.1 AH is an important contributor to NHL outcome. In contrast to A*01-B*08-TNF(-308A, the remaining alleles (Cw*07, DRB1*03, LTA+252G) associated with the 8.1 AH seem to be its passive components.

on behalf of the Polish Donor-Recipient Matching Study Group Among cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), some are sensitive to natural killer (NK) cell reactivity, described as the "missing self" recognition effect. However, this model disregarded the NK cell licensing effect, which highly increases the NK cell reactivity against tumor and is dependent on the coexpression of inhibitory killer cell immunoglobulin-like receptor (iKIR) and its corresponding HLA Class I ligand. We assessed clinical data, HLA and donor iKIR genotyping in 283 patients with myelo-and lymphoproliferative malignancies who underwent HSCT from unrelated donors. We found dramatically reduced overall survival (OS), progression free survival (PFS), and time to progression (TTP) among patients with malignant diseases with the lack of HLA ligand cognate with this iKIR involved in NK cell licensing in corresponding donor (events 83.3% vs. 39.8%, P 5 0.0010; 91.6% vs. 47.7%, P 5 0.00010; and 30.0% vs. 17.3%, P 5 0.013, for OS, PFS, and TTP, respectively). The extremely adverse PFS have withstand the correction when patient group was restricted to HLA mismatched donor-recipient pairs. The incidence of aGvHD was comparable in two groups of patients. In malignant patients after HSCT the missing HLA ligand for iKIR involved in NK cell licensing in corresponding donor ("missing licensing proof") induced extremely adverse survival of the patients due to the progression of malignancy and not to the aGvHD. Avoiding the selection of HSCT donors with the "missing licensing proof" in the malignant patient is strongly advisable.

Viral infections are the main cause of increased morbidity and mortality among recipients in allogeneic hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells fight virally infected cells provided directional activation of cytotoxicity. In this study, we analyzed the role of receptor‐ligand pairs that include inhibitory or activating killer cell immunoglobulin‐like receptors (KIRs) with their HLA class I ligands in the course of viral infections. The paper also presents an algorithm that allows performing automated inhibitory (i) KIR:HLA pairing and rechecking in the clinical setting. The obtained results indicate a significant adverse roles of reduced number of iKIR:HLA pairs (40% vs 9%; odds ratio [OR] = 6.67; P = .0057; 95% confidence interval [CI] 1.74‐25.62) and the presence of activating KIR:HLA pairs (15% vs 5%, OR = 3.58, P = .028, 95% CI 1.19‐10.73) in EBV infections post HSCT.