High-allelic variability in HLA-C mRNA expression: association with HLA-extended haplotypes.

Human leukocyte antigen (HLA)-C is a clinically relevant transplantation antigen in unrelated hematopoietic stem cell and cord blood transplantation. Furthermore, HLA-C antigens, as ligands for killer immunoglobulin-like receptors expressed on natural killer cells, have a central role in HIV control. Several studies have reported significant correlations between HLA-C mRNA and cell surface expression with polymorphisms in the 5'- and 3'-regions of the HLA-C locus. We determined HLA-C mRNA in blood donors by using locus as well as allele-specific real-time-PCR and focused the analysis on HLA-extended haplotypes. High inter-individual variability of mRNA expression was disclosed. A lower inter-individual variability for C*07:01 but a higher variability for C*06:02, C*04:01 and C*03:04 alleles were detected. The previously reported associations between HLA-C cell surface expression and -32 kb/-35 kb single nucleotide polymorphisms were not confirmed. Related and unrelated individuals sharing the same two A-B-C-DRB1 or B-C haplotypes show strikingly similar levels of HLA-C mRNA expression in each of the different haplotypic combinations tested. Altogether, our results suggest that HLA-C expression levels best correlate with the extended HLA haplotype rather than with the allotype or with polymorphisms in the 5'-region of the HLA-C locus.

Resolution of HLA-B*44:02:01G, -DRB1*14:01:01G and -DQB1*03:01:01G reveals a high allelic variability among 12 European populations.

Within the framework of the EU-funded HLA-NET action, an analysis of three G-group alleles, HLA-B*44:02:01G, DRB1*14:01:01G and DQB1*03:01:01G, was undertaken in 12 European populations. Ambiguities were resolved by polymerase chain reaction-sequence-specific amplification (PCR-SSP) or PCR-sequence-based typing (PCR-SBT) in a total of 5095 individuals. The results of the DRB1*14:01/14:54 ambiguity showed high relative ratios (24-53%) of DRB1*14:01 in Bulgarians, Croatians, Greeks, Italians and Slovenians, contrasting with low ratios (6-13%) in Austrians, Finnish, French, Hungarians, Norwegians and Swiss. Resolution of the B*44:02/44:27 ambiguity showed that B*44:27 had a high relative ratio in Slovenians (25.5%) and Bulgarians (37%) and low in French and Swiss (0.02-1%), and was not observed in Greeks and Italians. The highest relative ratio of DQB1*03:19 was found in Portuguese (11%), by contrast with low ratios (0-3%) in the other five populations. Analysis of the A, B, DRB1 phenotypes and family-derived haplotypes in 1719 and 403 individuals positive for either HLA-B*44:02G or DRB1*14:01G ambiguities, respectively, showed some preferential associations, such as A*26∼DRB1*14:01, B*35∼DRB1*14:01, B*38∼DRB1*14:01 and B*44:27∼DRB1*16. Because these ambiguities are located outside the peptide-binding site, they may not be recognized by alloreactive T-cells. However, because of strong linkage disequilibrium (LD), the DRB1*14:01 vs DRB1*14:54 and the B*44:02 vs B*44:27 mismatches are associated to DRB3-, and C-mismatches, respectively. These results are informative for algorithms searching unrelated hematopoietic stem cell donors. For B*44:27-positive patients, searches are expected to be more successful when requesting donors from Southeastern-European ancestry. Furthermore, the introduction of human leukocyte antigen (HLA)-typing strategies that allow resolving exon 4 (for class I) and exon 3 (for class II) polymorphisms can be expected to contribute significantly to population genetics studies.

Frequency and determinants of pregnancy-induced child-specific sensitization.

The aim of this study was to define the frequency and determinants of pregnancy-induced child-specific sensitization shortly after full-term delivery using sensitive single HLA-antigen beads (SAB) and high resolution HLA-typing of the mothers and their children (n = 301). A positive SAB result was defined by a background normalized ratio >1 or a mean fluorescence intensity (MFI) >300, >500 and >1000, respectively. The overall frequency of pregnancy-induced sensitization determined by SAB shortly after full-term delivery was between 45% (MFI > 1000 cut-off) and 76% (ratio cut-off). The rate of child-specific sensitization at the HLA-A/B/C/DRB1 loci was between 28% (MFI > 1000 cut-off) and 38% (ratio cut-off). The number of live birth was associated with a higher frequency of sensitization, which was driven by child-specific, but not third party HLA-antibodies. There was a clear hierarchy of sensitization among the investigated loci (B-locus: 31%; A-locus: 26%; DRB1-locus: 20%; C-locus: 15%; p < 0.0001). Some mismatched paternal HLA-antigens led to a significantly higher rate of sensitization than the average (e.g. HLA-A2, HLA-B49, HLA-B51, HLA-C*15). Furthermore, the mother's own HLA-phenotype--especially HLA-A/B homozygosity--was associated with a higher rate and broadness of sensitization. The number of mismatched HLA-A/B/C eplets strongly correlated with the rate of child-specific class I sensitization.

Lack of recognition of HLA class I mismatches outside α1/α2 domains by CD8+ alloreactive T lymphocytes: the HLA-B44 paradigm.

Transplantation with hematopoietic stem cells (HSC) from a donor with a single human leukocyte antigen (HLA) mismatch can be proposed to those patients lacking an HLA identical sibling donor or an unrelated donor matched for the HLA-A, -B, -C, DRB1, DQB1 loci. Incompatibilities at HLA classes I and II loci are associated with an increased risk of graft-versus-host disease (GVHD) and mortality, although no consensus exists yet on the relative importance of specific allele disparities on clinical outcome. Donor search algorithms are now complicated by the growing number of new HLA alleles, in particular those that differ outside the peptide-binding site of the HLA molecules. We report here an in vitro cellular assay to quantify CD8+CD137+ alloreactive cytotoxic T lymphocytes (CTLs) in a one-way mixed lymphocyte reaction. Two unique combinations with a single HLA mismatch in the HLA-B44 serotype differing by one amino acid in the α3 domain were investigated. We show that the B*44:27 versus B*44:02 mismatch was not recognized by CTLs in both directions. At days 10 and 20, the frequency of CD8+CD137+T cells was comparable to that measured in the autologous stimulation (0.3-3.9%). A B*44:02 versus B*44:03 mismatch was, however, well recognized at day 10 (7.2%) and day 20 (17.8%). This is the first demonstration that a single HLA-B mismatch involving a residue outside the peptide-binding site is not recognized in an in vitro functional assay and may probably be considered as a permissive incompatibility in vivo.

Human leukocyte antigen-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in an Albanian population from Kosovo.

HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genotyping was performed in a sample of Albanian population from Kosovo. The comparison of the respective allele frequencies through Fst analysis resulted in a close relationship with the Albanians from Albania, the Bulgarians, FYROM Macedonians and Greeks, while the other neighbouring populations are slightly more distant.

16th IHIW: international histocompatibility working group in hematopoietic cell transplantation.

The International Histocompatibility Working Group is a collaborative international effort to understand the HLA and non-HLA genetics of the transplantation barrier. The Working Group is comprised of experts in the fields of histocompatibility and immunogenetics, hematopoietic cell transplantation and outcomes research. Data for 25 855 unrelated donor transplants were submitted in support of research studies for the 16th International Histocompatibility Workshop. Active investigation is in progress in seven key areas: the impact of HLA matching, role of race and ethnicity, identification of permissible HLA mismatches, haplotype-associated determinants, minor histocompatibility antigens, immune response genes and KIR genetics. New hypotheses for the 16th workshop were developed for immunogenetic studies in cord blood and haploidentical-related donor transplantation.

16(th) IHIW: analysis of HLA population data, with updated results for 1996 to 2012 workshop data (AHPD project report).

We present here the results of the Analysis of HLA Population Data (AHPD) project of the 16th International HLA and Immunogenetics Workshop (16IHIW) held in Liverpool in May-June 2012. Thanks to the collaboration of 25 laboratories from 18 different countries, HLA genotypic data for 59 new population samples (either well-defined populations or donor registry samples) were gathered and 55 were analysed statistically following HLA-NET recommendations. The new data included, among others, large sets of well-defined populations from north-east Europe and West Asia, as well as many donor registry data from European countries. The Gene[rate] computer tools were combined to create a Gene[rate] computer pipeline to automatically (i) estimate allele frequencies by an expectation-maximization algorithm accommodating ambiguities, (ii) estimate heterozygosity, (iii) test for Hardy-Weinberg equilibrium (HWE), (iv) test for selective neutrality, (v) generate frequency graphs and summary statistics for each sample at each locus and (vi) plot multidimensional scaling (MDS) analyses comparing the new samples with previous IHIW data. Intrapopulation analyses show that HWE is rarely rejected, while neutrality tests often indicate a significant excess of heterozygotes compared with neutral expectations. The comparison of the 16IHIW AHPD data with data collected during previous workshops (12th-15th) shows that geography is an excellent predictor of HLA genetic differentiations for HLA-A, -B and -DRB1 loci but not for HLA-DQ, whose patterns are probably more influenced by natural selection. In Europe, HLA genetic variation clearly follows a north to south-east axis despite a low level of differentiation between European, North African and West Asian populations. Pacific populations are genetically close to Austronesian-speaking South-East Asian and Taiwanese populations, in agreement with current theories on the peopling of Oceania. Thanks to this project, HLA genetic variation is more clearly defined worldwide and better interpreted in relation to human peopling history and HLA molecular evolution.

Detection of anti-HLA antibodies by solid-phase assay in kidney transplantation: friend or foe?

Pre-formed and de novo anti-human leukocyte antigen (HLA) antibodies induce antibody-mediated rejection and are also involved in mechanisms leading to chronic graft nephropathy. The detection of anti-HLA antibodies by solid-phase assay (SPA) has revolutionized the management of immunized patients before and after kidney transplantation. Characterized by high sensitivity and specificity, the clinical relevance of anti-HLA antibodies by SPA has to be clarified. The presence of donor-specific antibody at the epitope level, their titer, and the use of different crossmatch technologies could help to determine which of the anti-HLA antibodies are friends and which are foes in kidney transplantation. In this review, we summarize the current state of the art on this debated topic, and give clinical guidelines for the management of antibody detection pre- and post-transplantation, based on these evidences and our own clinical expertise.

Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations.

HLA-NET (a European COST Action) aims at networking researchers working in bone marrow transplantation, epidemiology and population genetics to improve the molecular characterization of the HLA genetic diversity of human populations, with an expected strong impact on both public health and fundamental research. Such improvements involve finding consensual strategies to characterize human populations and samples and report HLA molecular typings and ambiguities; proposing user-friendly access to databases and computer tools and defining minimal requirements related to ethical aspects. The overall outcome is the provision of population genetic characterizations and comparisons in a standard way by all interested laboratories. This article reports the recommendations of four working groups (WG1-4) of the HLA-NET network at the mid-term of its activities. WG1 (Population definitions and sampling strategies for population genetics' analyses) recommends avoiding outdated racial classifications and population names (e.g. 'Caucasian') and using instead geographic and/or cultural (e.g. linguistic) criteria to describe human populations (e.g. 'pan-European'). A standard 'HLA-NET POPULATION DATA QUESTIONNAIRE' has been finalized and is available for the whole HLA community. WG2 (HLA typing standards for population genetics analyses) recommends retaining maximal information when reporting HLA typing results. Rather than using the National Marrow Donor Program coding system, all ambiguities should be provided by listing all allele pairs required to explain each genotype, according to the formats proposed in 'HLA-NET GUIDELINES FOR REPORTING HLA TYPINGS'. The group also suggests taking into account a preliminary list of alleles defined by polymorphisms outside the peptide-binding sites that may affect population genetic statistics because of significant frequencies. WG3 (Bioinformatic strategies for HLA population data storage and analysis) recommends the use of programs capable of dealing with ambiguous data, such as the 'gene[rate]' computer tools to estimate frequencies, test for Hardy-Weinberg equilibrium and selective neutrality on data containing any number and kind of ambiguities. WG4 (Ethical issues) proposes to adopt thorough general principles for any HLA population study to ensure that it conforms to (inter)national legislation or recommendations/guidelines. All HLA-NET guidelines and tools are available through its website http://hla-net.eu.

Basic characteristics and safety of donation in related and unrelated haematopoietic progenitor cell donors - first 10 years of prospective donor follow-up of Swiss donors.

Since July 2007 prospective life-long follow-up (FU) for unrelated (URD) and related donors (RD) is mandatory in Switzerland and data on every allogeneic haematopoietic progenitor cell (HPC) donation are collected prospectively. We report the real-world experience of HPC donation during a 10-year study period (01.07.2007-30.06.2017) with basic characteristics and FU data. 1105 donors underwent 1155 HPC donation procedures. Eighty percent of first donations performed by 802 (73%) RDs and 303 (27%) URDs were peripheral blood stem cells (PBSC), 20% bone marrow (BM). Male donors were over-represented as URD (60% male vs 40% female). Main differences between RDs and URDs concerned age and pre-existing health disorders. RDs were significantly older at first donation (median age 48 years) compared to URD (34 years, p < 0.0001) and had more pre-existing health problems: 25% vs 9% in URD (p < 0.0001). No fatal complications occurred, collection related severe adverse events (SAE) after first donation were not significantly different between groups (RD 1.2%, URD 0.99%), incidence rates for neoplastic and autoimmune diseases did not exceed the rates of the general population. RDs are a more heterogeneous and potentially more vulnerable group, but if donor evaluation is performed appropriately, HPC donation is still safe.

Immunogenetics of hematopoietic stem cell transplantation: the contribution of microsatellite polymorphism studies.

Polymorphisms of short tandem repeats of <10 nucleotides, or microsatellites (Msat), are largely used for post-transplant chimerism analyses in clinical hematopoietic stem cell transplantation (HSCT). Compared to single nucleotide polymorphisms (SNP), they have the advantage of a higher degree of allelic polymorphism and thus a potentially larger degree of informativity. Msat markers contribute to approximately 3% of the human genome and have been highly informative in disease association studies, population genetics, forensic medicine and organ and HSC transplantation. They allowed to expand our knowledge of the haplotypic structure of the HLA complex, including the noncoding sequences in the MHC, and to reach a better characterization of immunological phenotypes. Among the different immunogenetic studies in HSCT patients reviewed here, four Msat loci linked to cytokine genes have been analysed by a number of laboratories as potential candidates markers for HSCT outcome: IFNG, TNFd, IL-10(-1064) and IL-1RN. The low patient numbers and high diversity of clinical parameters account for some heterogeneity of the results. Among the trends starting to emerge from these studies, specific TNFd Msat alleles seem to be associated with acute graft-versus-host disease and mortality. Patient/donor Msat incompatibilities have also been used as surrogate markers to map biologically relevant polymorphisms, with a main focus on MHC-resident genetic variation. High throughput SNP typing and next-generation sequencing technologies will allow acquisition of large-scale genomic data and should allow refined analyses of clinically relevant genotypes in the transplantation settting, although the heterogeneity of the study cohorts will remain an issue. The analysis of Msat polymorphisms may still have a place in functional studies on the impact of Msat diversity in the control of immune response gene expression.

Functional polymorphism of each of the two HLA-DR beta chain loci demonstrated with antigen-specific DR3- and DRw52-restricted T cell clones.

HLA-DR3- and HLA-DRw52-associated functional polymorphism was investigated with selected tetanus toxoid (TT)-specific T cell clones. We have shown earlier that HLA-DR antigens are encoded by two distinct loci, DR beta I and DR beta III. The alloantigenic determinant(s) defined by the serological HLA-DR3 specificity map to the former, while the supratypic HLA-DRw52 determinants map to DR beta III. Furthermore, we have recently recognized by DNA sequencing three alleles of HLA-DRw52 at locus DR beta III, referred to as 52 a, b, and c. Our objective was to correlate the pattern of T cell restriction with the gene products of individual DR beta chain loci and with the three newly described alleles of locus DR beta III. Among the selected T cell clones, 5 reacted exclusively when TT was presented by HLA-DR3+ APCs (TT-DR3-APC). In contrast, two T cell clones were stimulated by TT-DRw52-APC. More specifically, these two T cell clones (Clones 10 and 16) were stimulated by different subsets of TT-DRw52-APC. Clone 16 responded to some DR3 and TT-DRw6-APC, while clone 10 was stimulated by other TT-DR3 and TT-DRw6, and all TT-DR5-APC. This same pattern of DRw52 restriction was found in panel, as well as in family studies. Because this suggested a correlation with the pattern of DRw52 polymorphism observed earlier by DNA sequencing and oligonucleotide hybridization, the APC used in these experiments were typed for the 52 a, b, and c alleles of locus DR beta III by allele-specific oligonucleotide probes. This distribution overlapped exactly with the stimulation pattern defined by the T cell clones. Clone 16 responded to TT-52a-APC, clone 10 to TT-52b-APC, and both clones to a TT-52c-APC. The response of the T cell clones was inhibited differentially by mAbs to DR. Raising TT concentration, or increasing HLA-class II expression with INF-gamma both affected the magnitude of response of the TT-specific clones but did not modify their specificities. These results demonstrate that a restriction specificity can be attributed to the DR beta III locus and illustrate the functional relevance of the polymorphism observed at this locus. This is of special interest in view of the striking difference in the pattern of structural diversity among alleles of DR beta I and DR beta III.

Analysis of the HLA population data (AHPD) submitted to the 15th International Histocompatibility/Immunogenetics Workshop by using the Gene[rate] computer tools accommodating ambiguous data (AHPD project report).

During the 15th International Histocompatibility and Immunogenetics Workshop (IHIWS), 14 human leukocyte antigen (HLA) laboratories participated in the Analysis of HLA Population Data (AHPD) project where 18 new population samples were analyzed statistically and compared with data available from previous workshops. To that aim, an original methodology was developed and used (i) to estimate frequencies by taking into account ambiguous genotypic data, (ii) to test for Hardy-Weinberg equilibrium (HWE) by using a nested likelihood ratio test involving a parameter accounting for HWE deviations, (iii) to test for selective neutrality by using a resampling algorithm, and (iv) to provide explicit graphical representations including allele frequencies and basic statistics for each series of data. A total of 66 data series (1-7 loci per population) were analyzed with this standard approach. Frequency estimates were compliant with HWE in all but one population of mixed stem cell donors. Neutrality testing confirmed the observation of heterozygote excess at all HLA loci, although a significant deviation was established in only a few cases. Population comparisons showed that HLA genetic patterns were mostly shaped by geographic and/or linguistic differentiations in Africa and Europe, but not in America where both genetic drift in isolated populations and gene flow in admixed populations led to a more complex genetic structure. Overall, a fruitful collaboration between HLA typing laboratories and population geneticists allowed finding useful solutions to the problem of estimating gene frequencies and testing basic population diversity statistics on highly complex HLA data (high numbers of alleles and ambiguities), with promising applications in either anthropological, epidemiological, or transplantation studies.

HLA-B51 and haplotypic diversity of B-Cw associations: implications for matching in unrelated hematopoietic stem cell transplantation.

In unrelated hematopoietic stem cell transplantation (HSCT), human leukocyte antigen (HLA)-C locus incompatibilities occur frequently and are associated with increased risk of posttransplant complications. Because HLA-B51 is associated with a high rate of Cw disparities, we performed a comprehensive four-digit typing analysis of 140 ABCDRB1 B51 genotypes proven by pedigree analysis and 311 unrelated donors selected for 75 B51-positive patients. In addition, 145 A1/Ax-B8/B51-DR3/DRx donors were HLA typed at a high-resolution level and tested for three microsatellite (Msat) polymorphisms located in the HLA class I and III regions. Based on these data sets, 182 different ABCDR haplotypes with 14 different B-Cw associations were detected. Rates of Cw mismatches were shown to be highly correlated with the ABDRB1 haplotypes. We have computed 21 B51 haplotypes that disclose a high probability of HLA-C allele matching and 30 haplotypes with a low (<25%) probability. The HLA-C allele frequency profiles were quite different in these two groups, with a more heterogeneous distribution in the low matching probability group. HLA-Cw*1502 was inversely correlated with the likelihood to identify a Cw-mismatched donor: it was present in 61% of the high vs 18% of the low probability group (P < 0.0001). The analysis of three Msats in the class I and III regions showed a higher allelic diversity in B51-positive haplotypes compared with the conserved A1-B8-DR3 haplotype. HLA-B51 haplotypes therefore exhibit a high diversity at the level of B-Cw associations and of non-HLA polymorphisms in the class I and III regions. Such heterogeneity negatively impacts on overall matching in HSCT.

Sequence of a novel HLA-A2 allele in a haematopoietic stem cell donor of the international registry.

We report here the sequence of a new human leucocyte antigen-A2 allele, A*9251, identified in a volunteer haematopoietic stem cell donor of the international registry. A*9251 differs from A*02010101 by two nucleotides at codons 113-114, resulting in a single His>Asp substitution at codon 114.

A bioinformatics approach to ascertaining the rarity of HLA alleles.

A project of the 15th International Histocompatibility Workshop examined the rarity of human leukocyte antigen (HLA) alleles. A section was constructed in the website, www.allelefrequencies.net to contain this data from different sources. A mechanism to search the data was implemented for use by any individual.

Early changes in the synthesis of nuclear and cytoplasmic proteins are induced by nerve growth factor in differentiating rat PC12 cells.

Differentiation of rat pheochromocytoma PC12 cells into neuron-like cells was induced by nerve growth factor (NGF) and changes in the apparent rate of synthesis of cellular proteins were analyzed. Attention was particularly focused on the first few hours of exposure to NGF before significant neurite outgrowth was detectable. Cultures were pulse-labeled for 1-h periods with [35S]methionine and proteins were extracted from various subcellular fractions and analyzed by one-dimensional gradient and two-dimensional equilibrium and nonequilibrium gel electrophoresis. The results showed that although the general level of protein synthesis remained constant, by 8 h NGF increased the apparent rate of synthesis of approximately 11 cytoplasmic and 5 nuclear proteins. For several of these proteins, the effect was apparently NGF-specific, since no induction was observed in dibutyryl cAMP-treated cells. Of interest was the following observation: of the five nuclear proteins, NGF increased the synthesis of two proteins with MrS of 56,000 [doublet] and 50,000 D that were associated with a biochemically and morphologically defined nuclear matrix fraction. A cytoplasmic protein, with an Mr of 92,000 D (pI 4.8) appeared to be induced de novo by NGF. NGF also decreased the rate of synthesis of several cytoplasmic and nuclear proteins of low molecular mass (less than 40,000 D). Since only 1-h pulses of [35S]methionine were used, and since experiments with actinomycin D showed that most of these NGF-induced early changes in rates of synthesis included a transcription-dependent step, it seems likely that early effects of NGF include activation of specific genes.

HLA allele and haplotype frequencies in the Albanian population and their relationship with the other European populations.

Human leucocyte antigen (HLA) alleles are very interesting markers in identifying population relationships. Moreover, their frequency distribution data are important in the implementation of donor-recipient registry programs for transplantation purposes and also in determining the genetic predisposition for many diseases. For these reasons, we studied the HLA class I and II allele and haplotype frequencies in 160 healthy, unrelated Albanian individuals originating from all regions of the country. The HLA genotyping was performed through a 2-digit resolution SSOP method. The data were analysed with Arlequin and Phylip programs. No deviation was found from the Hardy-Weinberg equilibrium. A total of 17 A*, 30 B*, 12 Cw*, 13 DRB1* and 5 DQB1* alleles were identified. The six most frequent HLA-A-B-DRB1 haplotypes were A*02-B*18-DRB1*11 (5.60%), A*02-B*51-DRB1*16 (4.74%), A*01-B*08-DRB1*03 (3.48%), A*24-B*35-DRB1*11 (2.77%), A*02-B*51-DRB1*13 (2.21%), A*24-B*35-DRB1*14 (1.89%). Interestingly, 12 HLA-A-B-Cw-DRB1-DQB1 haplotypes occurred at a frequency >1%. When compared with the other populations, a close relationship was found with North Greek, Bulgarian, Macedonian, Romanian, Turkish, Cretan, Serbian, Croatian and Italian populations. A higher differentiation in allele frequency level was found with Western Europe populations. These data are the first report of HLA allele and haplotype distribution in an Albanian population inside this country. When compared with other populations, their distribution frequencies show close similarities with neighbouring populations of the entire Balkan area.

Natural killer cell receptor repertoire and their ligands, and the risk of CMV infection after kidney transplantation.

Cytomegalovirus (CMV) infection is the most common viral complication after solid organ transplantation (SOT). Whilst current immunosuppression is known to impair antiviral-specific T-cell immunity in SOT, a potential role for natural killer (NK) cells not affected by immunosuppressive therapy remains to be determined. To address this, we compared the genotype of the NK immunoglobulin-like receptor (KIR) genes and their HLA cognate ligands to the rate of CMV infection in 196 kidney transplant recipients. We have shown that the absence of the HLA-C ligand for inhibitory KIR and the presence of activating KIR genes in the recipients were both associated with a lower rate of CMV infection after transplantation. In a cohort of 17 recipients with acute CMV infection, NK cells were phenotyped over a period of time after diagnosis by their expression profile of C-type lectin receptors and capacity to secrete IFN-gamma. The increased expression of the activating C-type lectin receptors NKG2C and NKG2D was paralleled by the decreased IFN-gamma secretion during the early phase of CMV infection. In conclusion, our findings suggest that KIR/HLA genotype and expression of NKG2C and NKG2D might play a significant role in regulating NK cell function and anti-CMV immunity after kidney transplantation.

A new HLA-DR4 allele, DRB1*0474, with an unusual residue at position 77.

We report here a new DR4 allele, DRB1*0474, identified in a volunteer hematopoietic stem cell donor of the Swiss National Registry. DRB1*0474 differs from DRB1*040701 by two nucleotide residues resulting in a single Thr --> Asn substitution at codon 77.