Bo Dupont

Nomenclature for factors of the HLA system, 2010

The WHO Nomenclature Committee for Factors of the HLA System met following the 14th International HLA and Immunogenetics Workshop in Melbourne, Australia in December 2005 and Buzios, Brazil during the 15th International HLA and Immunogenetics Workshop in September 2008. This report documents the additions and revisions to the nomenclature of HLA specificities following the principles established in previous reports (1–18).

Killer Ig-Like Receptor Haplotype Analysis by Gene Content: Evidence for Genomic Diversity with a Minimum of Six Basic Framework Haplotypes, Each with Multiple Subsets

Killer Ig-like receptor (KIR) genes constitute a multigene family whose genomic diversity is achieved through differences in gene content and allelic polymorphism. KIR haplotypes containing a single activating KIR gene (A-haplotypes), and KIR haplotypes with multiple activating receptor genes (B-haplotypes) have been described. We report the evaluation of KIR gene content in extended families, sibling pairs, and an unrelated Caucasian panel through identification of the presence or absence of 14 KIR genes and 2 pseudogenes. Haplotype definition included subtyping for the expressed and nonexpressed KIR2DL5 variants, for two alleles of pseudogene 3DP1, and for two alleles of 2DS4, including a novel 2DS4 allele, KIR1D. KIR1D appears functionally homologous to the rhesus monkey KIR1D and likely arose as a consequence of a 22 nucleotide deletion in the coding sequence of 2DS4, leading to disruption of Ig-domain 2D and a premature termination codon following the first amino acid in the putative transmembrane domain. Our investigations identified 11 haplotypes within 12 families. From 49 sibling pairs and 17 consanguineous DNA samples, an additional 12 haplotypes were predicted. Our studies support a model for KIR haplotype diversity based on six basic gene compositions. We suggest that the centromeric half of the KIR genomic region is comprised of three major combinations, while the telomeric half can assume a short form with either 2DS4 or KIR1D or a long form with multiple combinations of several stimulatory KIR genes. Additional rare haplotypes can be identified, and may have arisen by gene duplication, intergenic recombination, or deletions.

TRANSPLANTATION FOR ACUTE LEUKAEMIA WITH HLA-A AND B NONIDENTICAL PARENTAL MARROW CELLS FRACTIONATED WITH SOYBEAN AGGLUTININ AND SHEEP RED BLOOD CELLS

A new procedure for enrichment of marrow precursors and removal of T lymphocytes from large volumes of human bone marrow, involving initial differential agglutination of T lymphocytes and mature marrow elements with soybean agglutinin, followed by rosetting with sheep red blood cells, was used to fractionate marrow cells from an HLA-A, B, DR non-identical, MLC non-reactive, paternal donor for transplantation into an infant with acute leukaemia. This transplant became completely engrafted and resulted in full recovery of normal, donor-derived haematopoietic function without graft-versus-host disease, sustained for 11 weeks after transplantation, at which time the patients leukaemia recurred. Subsequently, the patient received chemotherapy and achieved a remission with regeneration of normal marrow cells of donor origin. The patients course demonstrated the potential of lectin-separated marrow grafts to restore durable haematopoiesis, without graft versus host disease, in a lethally irradiated allogeneic host.

The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order, haplotypes and allelic polymorphism

Summary: Recent genetic studies have established that the killer cell immunoglobulin‐like receptor (KIR) genomic region displays extensive diversity through variation in gene content and allelic polymorphism within individual KIR genes. It is demonstrated by family segregation analysis, genomic sequencing, and gene order determination that genomic diversity by gene content alone gives rise to more than 20 different KIR haplotypes and at least 40–50 KIR genotypes. In the most reductionist format, KIR haplotypes can be accommodated within one of 10 different prototypes, each with multiple permutations. Our haplotype model considers the KIR haplotype as two separate halves: the centromeric half bordered upstream by KIR3DL3 and downstream by 2DL4, and the telomeric half bordered upstream by 2DL4 and downstream by 3DL2. There are rare KIR haplotypes that do not fit into this model. Recombination, gene duplication, and inversion can however, readily explain these haplotypes. Additional allelic polymorphism imposes extensive individual variability. Accordingly, this segment of the human genome displays a level of diversity similar to the one observed for the human major histocompatibility complex. Recent application of immunogenetic analysis of KIR genes in patient populations implicates these genes as important genetic disease susceptibility factors.

Nomenclature for factors of the HLA system, 1991

Abstract The WHO Nomenclature Committee for factors of the HLA system met in Hakone after the Eleventh International Histocompatibility Workshop and Conference during November 1991 to consider additions and revisions to the nomenclature of specificities defined by both molecular and serological techniques following the principles established in previous reports (1 – 10).

CLOSE GENETIC LINKAGE BETWEEN HLA AND CONGENITAL ADRENAL HYPERPLASIA (21-HYDROXYLASE DEFICIENCY)

Congenital adrenal hyperplasia (C.A.H.) with 21-hydroxylase deficiency is an autosomal recessive disease. HLA genotyping of parents and children in six families in which more than 1 child had C.A.H. established that the gene responsible for 21-hydroxylase deficiency is closely linked to HLA. One patient had inherited a maternal HLA-A/B recombinant haplotype and studies in this family indicated that the abnormal gene is close to the HLA-B locus. The findings provide a method for identification of C.A.H. carriers and for prenatal diagnosis of affected children.

Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma.

Evasion of host immune responses is well documented for viruses and may also occur during tumor immunosurveillance. The mechanisms involve alterations in MHC class I expression, Ag processing and presentation, chemokine and cytokine production, and lymphocyte receptor expression. Epithelial tumors overexpress MHC class I chain-related (MIC) molecules, which are ligands for the activating receptor NKG2D on NK and T cells. We report that NK cells from patients with colorectal cancer lack expression of activating NKG2D and chemokine CXCR1 receptors, both of which are internalized. Serum levels of soluble MIC (sMIC) are elevated and are responsible for down-modulation of NKG2D and CXCR1. In contrast, high serum levels of CXC ligands, IL-8, and epithelial-neutrophil-activating peptide (ENA-78) do not down-modulate CXCR1. In vitro, internalization of NKG2D and CXCR1 occurs within 4 and 24 h, respectively, of incubating normal NK cells with sMIC-containing serum. Furthermore, natural cytotoxicity receptor NKp44 and chemokine receptor CCR7 are also down-modulated in IL-2-activated NK cells cocultured in MIC-containing serum—an effect secondary to the down-modulation of NKG2D and not directly caused by physical association with sMIC. The patients’ NK cells up-regulate expression of NKG2D, NKp44, CXCR1, and CCR7 when cultured in normal serum or anti-MIC Ab-treated autologous serum. NKG2D+ but not NKG2D− NK cells are tumoricidal in vitro, and in vivo they selectively traffic to the xenografted carcinoma, form immunological synapse with tumor cells, and significantly retard tumor growth in the SCID mice. These results suggest that circulating sMIC in the cancer patients deactivates NK immunity by down-modulating important activating and chemokine receptors.

Nomenclature for Factors of the HLA System, 1996

Recently a number of new genes have been identified within the HLA region including some whose functions are related to HLA class I and I1 genes. The Committee discussed what its strategy should be for the naming of these and further new Julia G. Bodmer, Steven 6. E. Marsh, Ekkehard D. Albert, Walter F. Bodmer, Ronald E. lontrop, Dominique Charron, Bo Dupant, Henry A. Erlich, Renee Fauchet, Bernard Mach, Wolfgang R. Mayr, Peter Parham, Takehlko Sasazuki, Geziena M. Th. Schreuder, Jack 1. Strominger, Arne Svejgaard and Paul la Terasaki

HLA-C–Dependent Prevention of Leukemia Relapse by Donor Activating KIR2DS1

BACKGROUND Of the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)-cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT. METHODS We assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donor KIR genotyping and evaluated the clinical effect of donor KIR genotype and donor and recipient HLA genotypes. RESULTS Patients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P=0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P=0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P=0.01). CONCLUSIONS Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C-dependent manner, and donor KIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.).

Nomenclature for Factors of the HLA System, 1994

1. Several clones should have been sequenced. 2. Sequencing should have been performed in both directions. 3. An accession number in a databank should have been obtained. 4. Full length sequences are preferable though not essential. 5. Where possible a paper should have been submitted for publication. 6. DNA or other material, in particular cell lines, should be made available in a publicly accessible repository or at least in the originating laboratory. Documentation on this will be maintained by the Nomenclature Committee.