Characterization of four murine monoclonal antibodies recognizing respectively HLA-A2 plus Aw69, HLA-B13, HLA-Bw4 and HLA-A28.
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Animals↗
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Primary structure shows HLA-B59 to be a hybrid of HLA-B55 and HLA-B51, and not a subtype of HLA-B8.
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Alleles↗
[Heterogeneity of HLA-Bw-35 and HLA-B12 antigens demonstrated by complex sera of anti-HLA-Bw4 and anti-HLA-Bw6].
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HLA Antigens↗
Molecular linkage of the HLA-DR, HLA-DQ, and HLA-DO genes in yeast artificial chromosomes.
Eight major histocompatibility complex (MHC) class II loci and the newly defined Y3/Ring 4 locus were isolated in overlapping yeast artificial chromosome (YAC) clones defining a 420-kb segment of human chromosome 6p21.3. YAC B1D12 spanning 320 kb contained seven of these loci from HLA-DRA to HLA-DQB2. A 330-kb YAC, A148A7, spanned from the HLA-DQA1 locus through the Y3/Ring 4 locus and extended at least 130 kb centromeric of YAC B1D12. Southern blotting demonstrated that YAC B1D12 derived from the HLA-DR3 haplotype and that YAC A148A7 derived from the HLA-DR7 haplotype of the heterozygous library donor. A third 150-kb YAC, A95C5, lay within this contig and contained only the HLA-DRA locus. A fourth 300-kb YAC, A76F11, was isolated by chromosome walking from the telomeric end of YAC B1D12. Probes isolated from the ends of the YAC genomic inserts have been used to confirm overlaps between the clones. These analyses demonstrated that the centromeric end of YAC A76F11 used the same genomic EcoRI cloning site as the telomeric end of YAC A95C5. YAC B1D12 used an EcoRI site only 2.1 kb telomeric of the aforementioned EcoRI site. These data suggest that certain EcoRI sites are used preferentially during construction of the library. These YACs complete the linkage of the DR and DQ subregions of the HLA complex in cloned DNA and provide the substrate for precise analysis of this portion of the class II region.
Base Sequence↗
Low incidence of acute graft-versus-host disease, using unrelated HLA-A-, HLA-B-, and HLA-DR-compatible donors and conditioning, including anti-T-cell antibodies.
BACKGROUND: Using unrelated bone marrow, there is an increased risk of graft-versus-host disease (GVHD). METHODS: HLA-A-, HLA-B-, and HLA-DR-compatible unrelated bone marrow was given to 132 patients. The diagnoses included chronic myeloid leukemia (n=43), acute lymphoblastic leukemia (n=29), acute myeloid leukemia (n=27), myelodysplastic syndrome (n=4), lymphoma (n=3), myeloma (n=1), myelofibrosis (n=1), severe aplastic anemia (n=12), and metabolic disorders (n=12). The median age was 25 years (range 1-55 years). HLA class I was typed serologically, and class II was typed by polymerase chain reaction using sequence-specific primer pairs. Immunosuppression consisted of antithymocyte globulin or OKT3 for 5 days before transplantation and methotrexate combined with cyclosporine. RESULTS: Engraftment was seen in 127 of 132 patients (96%). Bacteremia occurred in 47%, cytomegalovirus (CMV) infection in 49%, and CMV disease in 8%. The cumulative incidences of acute GVHD > or = grade II and of chronic GVHD were 23% and 50%, respectively. The 5-year transplant-related mortality rate was 39%. The overall 5-year patient survival rate was 49%; in patients with metabolic disorders and severe aplastic anemia, it was 61% and 48%, respectively. The disease-free survival rate was 47% in patients with hematological malignancies in first remission or first chronic phase and 38% in patients with more advanced disease (P=0.04). Acute GVHD was associated with early engraftment of white blood count (P=0.02). Poor outcome in multivariate analysis was associated with acute myeloid leukemia (P=0.01) and CMV disease (P=0.04). CONCLUSION: Using HLA-A-, HLA-B-, and HLA-DR-compatible unrelated bone marrow and immunosuppression with antithymocyte globulin, methotrexate, and cyclosporine, the probability of GVHD was low and survival was favorable.
Adolescent↗
Differential expression of HLA-DR, HLA-DP, and HLA-DQ antigenic determinants of the major histocompatibility complex in human endometrium.
We reported on the expression of HLA-DR molecules of the major histocompatibility complex in human endometrium. We now report on the expression of two other class II molecules, the HLA-DP and HLA-DQ determinants. These molecules were localized by monoclonal antibodies in 11 proliferative and 12 secretory endometria by avidin-biotin-complex (ABC) procedure. The expression of all three molecules was invariable and consistent throughout the entire menstrual cycle in endothelial and lymphoid cells. HLA-DR molecules were expressed in endometrial epithelium, particularly in the basalis in the mid to late proliferative phases of the cycle. In contrast, through the entire menstrual cycle, the expression of HLA-DP and HLA-DQ antigenic determinants was absent, and only occasionally a focal expression of these molecules was seen in endometrial epithelium. The in vitro induction of expression of the class II molecules in human endometrial epithelial cell cultures (HEE) by IFN-gamma was dose-dependent. After treatment with low doses of IFN-gamma, these cells primarily expressed HLA-DR molecules in vitro. The differential expression of the molecules of the major histocompatibility complex in human endometrial epithelium in vivo may be due to the differential sensitivity of th epithelium in response to cytokine(s).
Antibodies, Monoclonal↗
Endogenous expression and HLA stabilization assay of Plasmodium falciparum CTL epitope minigene in human HLA-A2. 1 and HLA-B51 cells.
OBJECTIVE: To evaluate the Plasmodium falciparum CTL epitope vaccines in HLA class I allele specific human cell lines that have high frequency among Chinese population. METHODS: Synthesized oligonucleotides encoding for P. f. CTL epitope genes, constructed eukaryotic expression plasmids, transfected the minigenes into HLA class I allele specific human cell lines and identified endogenous expressing of the minigenes by RT-PCR and HLA stabilization assay. RESULTS: Two mini-genes encoding Plasmodium falciparum CTL epitopes were designed and cloned, respectively, into an eukaryotic expressing vector to form TR26 which was restricted to HLA-B51, SH6 which was restricted to HLA-A2. 1, and TS, which had the two aforementioned mini-genes fused in tandem. All of these CTL epitope genes were transfected and endogenously expressed in respective cell lines containing appropriate HLA molecules. The obviously increased expressions of HLA class I molecules were detected in the transfected cell lines. It was demonstrated that the two discrete Plasmodium falciparum epitope genes were effectively processed and presented, and the close proximity of the two epitope genes in one chain as in mini-gene TS did not interfere with the processing and presenting of each epitope gene in corresponding cell line. CONCLUSION: A successful expression and presentation of multiple CTL epitope mini-gene in MHC class I allele specific human cell lines were demonstrated by an in vitro assay, which could be corresponding to the vaccination of CTL vaccines in people with different MHC I molecules. This work also suggested the possibility of constructing a multiple CTL epitope Plasmodium falciparum DNA vaccine that could cover most of Chinese population.
Animals↗
The HLA-AW24 gene: sequence, surroundings and comparison with the HLA-A2 and HLA-A3 genes.
A cosmid clone containing two class I sequences was found to cause expression of the HLA-AW24 protein after transfection into mouse L cells. The restriction map of this cosmid shows extensive homology over 26 kb with the map of the HLA-A3 region obtained from cosmids of the same library, constructed with DNA from an HLA-A3/HLA-AW24 heterozygote, but diverges over the remaining 14 kb. The HLA-AW24 gene was subcloned from this cosmid and its nucleotide sequence was determined. Amino acid and, more strikingly, nucleotide sequence comparisons with other HLA alleles indicate that the A locus alleles are more closely related to each other than to alleles from other HLA loci. A very skewed distribution of silent substitutions is apparent, and the occurrence of clustered multiple substitutions hints at gene-conversion-like events.
Alleles↗
Relationships between 34 HLA-A, HLA-B and HLA-DR antigens and three serological markers of viral infections in alcoholic cirrhosis.
In order to study the genetic risk of alcoholic cirrhosis, the frequency of 26 HLA-A and -B antigens was compared in 184 normal controls, 175 alcoholic cirrhotic patients and 83 alcoholic patients with hepatic steatosis of carefully selected ethnic origin. Eight HLA-DR antigens were also determined in 95 subjects of the normal control group and 63 patients of the alcoholic cirrhosis group. The incidence of hepatitis B virus antibodies (anti-HBc and anti-HBs) was defined in 74 patients of the alcoholic steatosis group, 170 patients of the alcoholic cirrhosis group and 111 normal controls different from the previously mentioned normal control group. The incidence and the titers of cytomegalovirus and rubella antibodies were also determined in 93 patients of the alcoholic cirrhosis group and the 111 normal controls. Serum immunoglobulin concentrations were measured in the same 93 cirrhotic patients. Compared with the controls, the alcoholic cirrhosis group revealed a significantly higher frequency of HLA-B15 (21.7 vs. 9.8%, p less than 0.00025, corrected p less than 0.050) and HLA-DR4 (38.1 vs. 17.9%, p less than 0.005, corrected p less than 0.050) and a significantly lower frequency of HLA-B13 (2.9 vs. 11.4%, p less than 0.025, corrected p less than 0.050). As for the frequency of all other HLA antigens, there was no significant difference between the three groups (normal controls, alcoholic cirrhosis and alcoholic steatosis).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
HLA-A, -B, -C, -DR, -DQ typing in a population group of Senegal: distribution of HLA antigens and HLA-DRB1*13 and DRB1*11 subtyping by PCR using sequence-specific primers (PCR-SSP).
One-hundred-and sixteen Senegalese Serere were typed for HLA antigens and compared with other ethnic groups in Gambia. We did not find significant differences (Fisher's exact test; P < 0.01) in the HLA antigens distribution between the Serere and Mandinka groups in Senegal and the Serere, Mandinka and Wolof in The Gambia. The most common HLA haplotypes found (P < 0.01; Chi square with Yates' correction) were: A1, B8; A2, B51; A32, B44; A33, B58; A2, Cw2; A2, Cw4; A33, Cw3; A2, DR17; A10, DR10; B35, Cw4; B53, Cw6; B57, Cw3; B65, Cw8; B50, DR15; B52, DR4; Cw2, DR17; DR7, DQ2; DR18, DQ4. The HLA-DRB1*13 and DRB1*11 alleles were subtyped by PCR-SSP and the frequencies of these alleles in the studied population given. HLA-DRB1*1304 and DRB1102 were the most common alleles found respectively 15.0 and 18.5%.
DNA Primers↗
A continuous restriction map from HLA-E to HLA-F. Structural comparison between different HLA-A haplotypes.
The class I region of the human major histocompatibility complex contains genes encoding the classical transplantation antigens (HLA-A, B, and C), at least three new class I genes (HLA-E, F, and G) and many class I pseudogenes (including HLA-H). By pulse field gel electrophoresis and using five rare cutter enzymes, we have constructed a precise and continuous map of 1200 kilobases (kb) around HLA-A. The blots were hybridized with HLA-A, E, and F-specific probes and with new probes derived from yeast artificial chromosomes and cosmids of the class I region. We have compared the genomic organization of the same 1200 kb in three homozygous lymphoblastoid cell lines corresponding to three different HLA haplotypes (A3, A24, and A31). The differences in size observed may have been caused by insertions and deletions and may prove valuable in understanding the evolution of the HLA chromosomal region.
Genes, MHC Class I↗
Characterization of two new HLA-B alleles by sequence-based typing: HLA-B*0817 and HLA-B*1311.
In this brief communication we report the characterization of two new HLA-B variants officially named HLA-B*0817 and HLA-B*1311. The HLA-B*0817 allele was identified in a Caucasoid male candidate for renal transplantation in the North Italy Transplant program. The nucleotidic sequence of exons 2, 3 and 4 of this novel allele is identical to that of HLA-B*0804 except for three point mutations in exon 2: from A to G at position 259, from C to G at position 261 and from G to A at position 302. These mutations are responsible for two aminoacidic substitutions [Asn (r) Glu, codon 63, and Ser (r) Asn, codon 77]. HLA-B*1311 was found in a volunteer donor belonging to National Marrow Donor Program(R). This new variant is identical to that of HLA-B*1301 except for three nucleotide substitutions at positions 353, 355 and 369 leading to two aminoacidic variations from Ile to Thr at codon 94 and from Ile to Leu at codon 95 and a silent mutation at codon 99.
Alleles↗
HLA-Cw*1214 allele arisen via recombination between HLA-Cw*070201 and HLA-Cw*120201.
Allelic polymorphism of the major histocompatibility complex arises mostly from gene conversion. Intralocus gene conversion usually involves limited fragments of DNA, whereas recombination involving large fragments of DNA is considered to be a rare event. During routine sequencing-based typing of donors for the National Marrow Donor Program, a new HLA-C allele was identified in a Caucasian donor. The allele, HLA-Cw*1214, proved to be the product of recombination between HLA-Cw*070201 and HLA-Cw*120201. Exons 1, 2, the 3' end of exon 3 and exon 4 (with one mismatch) belong to HLA-Cw*120201, whereas part of exon 3 belongs to HLA-Cw*070201. Sequencing with primers based in exon 2 and exon 3 showed that intron 2 of the new allele also belonged completely to HLA-Cw*1202. The recombination event apparently occurred within exon 3 with the first point of recombination somewhere between codons 92 and 134 and the second one between codons 157 and 181.
Alleles↗
Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched related donors, and HLA-matched unrelated donors.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a proven curative therapy for many hematologic malignancies. HSCT from HLA-identical sibling donors (ISDs) is still the golden standard. For the remaining 70% of the patients lacking an ISD, alternative (partially) HLA-matched family donors (MFDs) and HLA-matched unrelated donors (MUDs) are now widely accepted. However, it is presently unclear whether outcome after HSCT from an MFD or an MUD is superior. Thus, the classical clinical end points after HSCT from an ISD (n = 138), MFD (n = 86), and MUD (n = 101) were compared by means of univariate and multivariate statistical analyses. MFD transplantations with HLA class II (DRB1 +/- DQB1) mismatches in graft-versus-host (GVH) direction showed an increased risk of grades II to IV graft-versus-host disease, and MFD transplantations with more than a single HLA class I (A +/- B +/- C) mismatch in host-versus-graft (HVG) direction were associated with a higher risk of graft failure. However, no significant difference in overall survival was detectable among the 3 study groups after adjustment for the main predictors of transplantation outcome. Thus, for patients lacking an ISD, an already identified MFD with an HLA-DRB1 +/- DQB1 mismatch in GVH or a combined HLA-A +/- B +/- C mismatch in HVG direction should be accepted only in clinically urgent settings that leave no time to identify an MUD.
Adolescent↗
Control of HLA-DR antigen gene expression at the pretranslational level: comparison of an HLA-DR-positive B lymphoblastoid cell line and its HLA-DR-negative variant.
An HLA-DR-positive human B lymphoblastoid cell line, T5-1, and its HLA-DR negative variant, 6.1.6, were studied to elucidate mechanisms resulting in the nonexpression of HLA-DR genes in 6.1.6. The cell lines were labeled with 35S-methionine in vivo, their proteins immunoprecipitated with a monoclonal HLA-DR-specific antibody, and their two-dimensional gel electrophoresis patterns compared. The T5-1 map showed DR-antigen heavy and light chains, while the 6.1.6 map showed neither chain. When the cells were labeled in the presence of tunicamycin, the two-dimensional map of T5-1 showed nonglycosylated heavy and light chains of DR antigen while that of 6.1.6 did not. RNA was extracted from T5-1 and 6.1.6 cells and translated in rabbit reticulocyte lysates. Two-dimensional gel analysis of the immunoprecipitated proteins from T5-1 revealed spots which were identified as HLA-DR light chain and I invariant on the basis of their precipitation by monoclonal and specific allo- and heteroantibodies, and their molecular weight and pI values. These spots were absent in the 6.1.6 maps, indicating that 6.1.6 has no detectable translatable messenger RNA for HLA-DR light chains. The addition of dog pancreas microsomes to the T5-1 cell-free translation mixture resulted in an increase in the molecular weight of the precursor HLA-DR proteins consistent with glycosylation. Together with earlier cell fusion studies showing that DR structural genes were intact in 6.1.6, these data suggested that the lesion in 6.1.6 is an alteration in a regulatory element required for transcription of DR genes or mRNA processing.
B-Lymphocytes↗
Generation and characterization of three new monoclonal antibodies detecting the allospecificities HLA-A2,w69, HLA-A3 and HLA-B13.
Immunization of balb/c mice with peripheral blood mononuclear cells of a leukemic patient possessing the antigens HLA-A2,3; B7,35 resulted in the polymorphic monoclonal antibody (moab) UL-101/68 (IgM) defining HLA-A3. Immunization of a second group of balb/c mice with the lymphoblastoid cell line BER homozygous for HLA-A2; B13 revealed two polymorphic moabs UL-39/10 (IgG3) specific for HLA-B13 and UL-39/24 (IgG2b) defining HLA-A2,w69. Immunoprecipitation and polyacrylamide gel electrophoresis with the two moabs of the IgG isotype confirmed the class I structure of the recognized antigens.
Acute Disease↗
HLA-A*0201, HLA-A*1101, and HLA-B*0702 transgenic mice recognize numerous poxvirus determinants from a wide variety of viral gene products.
In virus models explored in detail in mice, CTL typically focus on a few immunodominant determinants. In this study we use a multipronged approach to understand the diversity of CTL responses to vaccinia virus, a prototypic poxvirus with a genome approximately 20-fold larger than that of the model RNA viruses typically studied in mice. Based on predictive computational algorithms for peptide binding to HLA supertypes, we synthesized a panel of 2889 peptides to begin to create an immunomic map of human CTL responses to poxviruses. Using this panel in conjunction with CTLs from vaccinia virus-infected HLA transgenic mice, we identified 14 HLA-A*0201-, 4 HLA-A*1101-, and 3 HLA-B*0702-restricted CD8(+) T cell determinants distributed over 20 distinct proteins. These peptides were capable of binding one or multiple A2, A3, and B7 supertype molecules with affinities typical of viral determinants. Surprisingly, many of the viral proteins recognized are predicted to be late gene products, in addition to the early intermediate gene products expected. Nearly all of the determinants identified have identical counterparts encoded by modified vaccinia virus Ankara as well as variola virus, the agent of smallpox. These findings have implications for the design of new smallpox vaccines and the understanding of immune responses to large DNA viruses in general.
Animals↗
Fine specificity of human HLA-B7-specific cytotoxic T-lymphocyte clones. I. Identification of HLA-B7 subtypes and histotopes of the HLA-B7 cross-reacting group.
Three HLA-B7-specific cytotoxic T lymphocyte (CTL) clones are described. Their fine specificity is examined by extensive panel and family studies. Four CTL-defined subtypes of HLA-B7 could be found: HLA-B7.1, -B7.2, -B7.3, and -B7.4. Biochemical evidence was obtained in one-dimension isoelectric focusing for only two subtypes. The estimated subtype frequencies in the Caucasian population are presented. Furthermore, a linkage disequilibrium between HLA-A29 and HLA-B7.3 is suggested. The CTL clones exerted distinct "extra-reactivities", i.e., lysis of some non-B7 target cells. These extra reactivities could be assigned to the cross-reacting group of HLA-B7.
Cells, Cultured↗