Identification of a novel HLA-DRB1*11 allele: DRB1*1152.
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Alleles↗
Biomedical subjects
D Adorno
Publications and source records attributed to D Adorno.
B*3812: a new HLA-B38 variant identified by sequence-based typing.
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Alleles↗
A new HLA-CW*14 allele, Cw*140204, identified by allele-specific DNA amplification and sequencing.
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Alleles↗
Cytokine levels in amniotic fluid: a marker of preterm labor?
The aim of this study was to determine levels of Interleukin 6 (IL-6) in amniotic fluid at the beginning of the second trimester and to establish whether IL-6 can be used as a marker for premature birth as it would appear to be an important prenatal marker of chorionic inflammation. Thirty-three patients, between 16 and 19 weeks of gestation, who were undergoing amniocentesis to establish the presence or not of fetal genetic pathologies were enrolled into the study. Amniotic fluid (3 ml) was taken from each patient and used to perform enzyme-linked immunosorbent assays (ELISAs). The results were analyzed using the Mann-Whitney test and Pearson and Spearman coefficient. The patients were divided into three groups on the basis of the levels of IL-6 found: a) up to 450 pg/ml; b) between 450 and 900 pg/ml; c) over 900 pg/ml; These data were then evaluated alongside the date of parturition and the presence of any maternal or fetal pathologies. The results of our analyses, however, were inconclusive: levels of IL-6 were normal in patients presenting pathologies while obstetric pathologies were absent in patients with high levels of IL-6. In conclusion, this data would indicate that a different method or approach is required for the identification of a marker for premature birth.
Adult↗
Characterization of a novel HLA-Cw*02 variant, Cw*0208, in a Caucasian individual.
We describe an additional HLA-Cw*02 variant, HLA-Cw*0208, which has been identified in a renal transplant recipient of Caucasian origin (Italy). After performing preliminary serological typing, we analyzed exons 2 and 3 of the HLA-C locus polymorphism by cloning the amplified DNA and using a sequence-based typing method. The new allele differs from Cw*020202 by one nucleotide substitution at nucleotide 61 (G-->A) of exon 2, which translates to a difference of one amino acid at residue 21 (His-->Arg) of the HLA-C heavy chain. We propose that Cw*0208 was generated by a random point mutation in codon 21 from the Cw*020202 allele, or through gene conversion of Cw*020202 with another allele, probably the Cw*1205 and Cw*1602 alleles.
Alleles↗
Identification of a novel HLA-A*02 allele, A*027401*.
A novel HLA-A*02 allele was detected in a Caucasian patient from central Italy, requiring a hematopoietic cell transplantation. Direct sequencing identified a variation in one nucleotide position, which was confirmed by cloning. The name A*027401 was officially assigned by the WHO Nomenclature Committee in November 2004. A*027401 differs from A*02010101 by a single G to A substitution at nucleotide position 595 in exon 3. The new variant would lead to a nonsynonymous nucleotide change (GGG to AGG) at codon 175, resulting in a basic Arg in the alpha-helix of the alpha2-domain, in place of a non-polar Gly. The presence of an uncommon variation at a highly conserved nucleotide position could have implications in unrelated hematopoietic cell transplantation.
Alleles↗
Human leukocyte antigen-A, -B, and -Cw polymorphism in a Berber population from North Morocco using sequence-based typing.
Class I human leukocyte antigen (HLA) polymorphism was examined in a Berber population from North Morocco, named Metalsa (ME). All data were obtained at high-resolution level, using sequence-based typing. The most frequent alleles were: HLA-A*0201 and A*0101; HLA-B*44 (B*4403 and B*4402); B*0801 and the B*50 allele group (B*5001 and B*5002); HLA-Cw*0602; and Cw*07 group (Cw*070101, Cw*070102, Cw*0702, Cw*0704, and Cw*0706), and Cw*040101. The novel HLA-B*570302 allele was identified. It differs at position 486 and position 855 from B*570301, resulting in synonymous Thr and Val. The analysis also evidenced some alleles common in Africans (A*3402, A*6802, A*7401, B*1503, B*4102, B*4202, B*7801, B*5802, Cw*1701, and Cw*1703) and some uncommon alleles (A*3004, B*2702, B*2703, B*5001,02, B*3503, and Cw*0706). The predominant HLA-A-Cw-B-DRB1-extended haplotypes in ME population were A*0101-Cw*0501-B*4402-DRB1*0402, A*240201-Cw*0701-B*0801-DRB1*030101, A*2301-Cw*040101-B*4403-DRB1*040501, A*0201-Cw*040101-B*4403-DRB1*1302, and A*3002-Cw*0602-B*5002-DRB1*0406. This study demonstrates a strong relatedness of ME to other Moroccan and North African populations, some characteristics of sub-Saharan Africans and evidenced the influence of various immigrations during centuries. Nevertheless, this study highlights some unique genetic traits of the ME population compared to other ethnic groups within Morocco, which could be of great interest for clinical aims, transplantation, and diseases.
Adult↗
Identification of the novel allele B*4427 and a confirmatory sequence (B*44022).
This report presents a novel allele, HLA-B*4427, which was identified in a bone marrow donor of Caucasian origin, and a confirmatory sequence (B*44022). Sequence analysis revealed the new allele differs from B*44021 by a single nucleotide exchange at position 668 (C-->T), which is located in exon 4. At the protein level, it is the only B*44 variant to produce an Ala in place of a Val at codon 199. Its structure suggests that it may have originated from a point mutation in B*44021 or by gene conversion with a variety of HLA-B alleles. Cloning and sequencing of the allele B*44022 revealed a sequence identical to B*44021 and B*44 exon 4, with the codon GTC (Val) in position 199.
Alleles↗
CD44 ligation on peripheral blood polymorphonuclear cells induces interleukin-6 production.
Polymorphonuclear cells (PMNs) contribute to the initiation and progression of the immune response by mediating cytotoxicity, phagocytosis, and cytokine secretion. Because CD44 serves as a cytotoxic-triggering molecule on PMNs, it was hypothesized that it could also trigger cytokine production. In this study, the effect of anti-CD44 antibodies on interleukin-6 (IL-6) production in human PMNs was assessed. By using a reverse transcriptase-polymerase chain reaction, it was shown that PMNs stimulated with a mouse monoclonal or a rabbit polyclonal F(ab)(2) anti-CD44 transcribe IL-6 messenger RNA. A similar effect was obtained when an anti-CD44 antibody was replaced with hyaluronic acid (HA). Kinetic studies showed that anti-CD44 and HA induced IL-6 gene transcription, initiated 3 hours after stimulation, peaked between 12 and 24 hours, and disappeared after 48 hours. Analogous results were achieved when secreted IL-6 protein was measured by enzyme-linked immunosorbent assay in the PMN culture supernatants. To characterize which metabolic pathways regulated CD44-dependent IL-6 production in PMNs, an RNA polymerase inhibitor, actinomycin D, and 2 protein kinase inhibitors, such as genistein and staurosporine, were tested. Actinomycin D and genistein blocked IL-6 production, whereas staurosporine did not, suggesting that CD44-dependent IL-6 production requires gene transcription and tyrosine kinase activity. Furthermore, the relationship between CD44 and cytokines that affect PMN function, including interferon gamma (IFNgamma) and IL-2, was investigated. Without CD44 cross-linking, IFNgamma did not trigger IL-6 production. However, on CD44 cross-linking, IFNgamma produced a strong synergistic effect on IL-6 syntheses in human PMNs. (Blood. 2001;97:3621-3627)
Animals↗
Impact of donor-specific antibodies on chronic rejection occurrence and graft loss in renal transplantation: posttransplant analysis using flow cytometric techniques.
BACKGROUND: Improvements in immunosuppressive therapy have greatly reduced acute rejection (ARj) episodes, ensuring better short-term graft outcome, but have not modified long-term survival in renal transplantation. It is now well accepted that chronic rejection (CRj) can be determined by both immune and/or nonimmune mechanisms. The aim of this study was to evaluate the importance of the posttransplant humoral immune response towards mismatched HLA graft antigens in CRj occurrence and graft outcome. METHODS: Serum samples from 120 nonpresensitized renal transplant recipients were prospectively screened for 1 year after surgery by means of flow cytometry cross-match (FCXM) and FlowPRA beads (microbeads coated with purified HLA class I and class II antigens) assays. All transplants were followed-up for 2 years or until graft removal. RESULTS: FCXM monitoring identified donor-specific antibodies (DS-Abs) in 29 (24.2%) of 120 transplanted patients. Correlation with clinical data highlighted a higher incidence of ARj in DS-Abs-positive patients compared to negative patients (62% vs. 13%, P<0.00001). Furthermore, graft failure occurred more frequently among FCXM-positive patients than among negative patients (34% vs. 1%, P<0.00001). The deleterious effect of DS-Abs on graft function was confirmed by serum creatinine levels 2 years after transplantation. These were in fact higher in subjects producing DS-Abs than in subjects with only ARj (mean creatinine: 2.5+/-1.3 mg/dL vs.1.7+/-0.5 mg/dL, P=0.04). FlowPRA analysis of DS-Ab HLA specificity highlighted the presence of anti-HLA class I antibodies in 85% of FCXM-positive patients, who also presented with a higher incidence of HLA-B mismatches than FCXM-negative patients (1.23+/-0.66 vs. 0.92+/-0.59, P=0.02). CONCLUSIONS: Flow cytometric techniques are precious tools for investigating the activation of the humoral response against HLA antigens of the graft in renal transplantation. DS-Abs production has a worse impact on organ function and survival than ARj episodes. These findings represent further proof of the threat posed by DS-Abs on long-term graft function and draw attention to the need for a specific immunosuppressive therapy aimed at counteracting the different kinds of immune activation toward graft.
Adult↗
Cell cycle control in cellular homeostasis during the immune response: interactions between TH1, TH2 cytokines, and Bcl2 and p53 molecules.
Cytokine regulation of lymphocyte survival may play an important role in the control of the cell cycle during the immune response both in health and disease. Expression of the Bcl2 gene promotes cell survival by countering apoptosis stimuli. The p53 protein has been implicated in the control of the cell cycle, in the synthesis and repair of DNA and in programmed cell death. TH1 and TH2 cytokines exert a mutual cross-regulation on the precursors of TH1- or TH2-type effector cells which are important mediators in directing the immune system towards the appropriate response. TH1 and TH2 cytokines have also been implicated in the modulation of the expression of cell cycle regulator genes. Therefore, the study of the relationships between TH1 and TH2 cytokines and Bcl2 and p53 molecules in healthy subjects could lead to a better understanding of the physiological regulation of the immune response and identify markers for prognostic and diagnostic indices and biotherapeutic treatment. We determined the serum levels of cytokines (IL2, IFN gamma, IL4, IL10, IL5, IL6, IL1 beta, TNF alpha, IL8), soluble receptors (sIL2R, sIL6R), Bcl2-protein and p53-antibody in a group of healthy subjects. Multivariate statistical analyses were used to study the cytokine network relationships with Bcl2-protein and p53-antibody, as they allow a simultaneous evaluation of all variables which reflects the physiological situation. Our overall results suggest that relationships exist between TH1 and TH2 cytokines and the Bcl2-protein and p53-antibody in physiological conditions. This information could now be used in experimental studies to create diagnostic and prognostic indices for the monitoring of health and disease.
Adult↗
Interleukin 1-beta modulates the effects of hypoxia in neuronal culture.
In order to study the role of interleukin-1beta (IL-1beta) in homeostasis, hypoxia and recovery of neuronal cells, we studied the expression and release of tumor necrosis factor-alpha (TNF-alpha) and nerve growth factor (NGF), in relation to the presence or absence of this cytokine in culture medium. Moreover, we evaluated cell mortality in the same conditions. For this aim, we used untreated and IL-1beta pre-immunoneutralized hippocampal neuronal cultures exposed to mild hypoxic stress and left to reoxygenate. Semiquantitative reverse-transciptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) determined gene expression and protein levels. Mild hypoxic stress provokes a decrease in both the expression and release of TNF-alpha and NGF. IL-1beta neutralization results in an inversion of this pattern since treated hypoxic cultures exhibited an increase of both expression and release of NGF. In pretreated hypoxic cells the increased expression of TNF-alpha was not followed by a rise in release. Reoxygenation reversed the observed effects in both cultures and the levels of cytokine expression and release were approaching control values. Our data show that in physiological conditions IL-1beta may have a neuroprotective action through positive modulation of NGF. Contrary to that, in presence of insult, IL-1beta may have an opposite role, since neutralization provoked an increase of expression and release of NGF. In addition, we demonstrated that neuronal cells are biochemically capable, not only of maintaining and recovering the homeostasis, but also of activating the appropriate response to insult. IL-1beta may have a pivotal role in this mechanism through the modulation of NGF and to a lesser degree of TNF-alpha.
Animals↗
Posttransplant donor-specific antibody characterization and kidney graft survival.
This study was designed to investigate the clinical relevance of donor-specific antibodies (DS-Abs) and their influence on graft survival. Among 106 patients who underwent cadaveric kidney donor transplantation and were monitored by flow cytometry crossmatch (FCXM) during the 1st posttransplantation year, 25 (23.6%) resulted positive for DS-Ab production. During a 2-year follow up only 12 of the 81 FCXM-negative patients (14.8%) suffered rejection vs 17 of 25 FCXM-positive patients (68%; P = 0.00001). Correlating graft loss to DS-Ab production, 9 FCXM-positive patients lost the graft vs only 1 among the FCXM-negative patients. A worse graft function was evidenced in FCXM-positive subjects who had also suffered rejection episodes than in those which had acute rejection but did not produce DS-Abs. A high incidence of HLA-AB mismatches was found in FCXM-positive subjects which produced anti-class I antibodies. FCXM appears useful in estimating posttransplant alloimmune response. Moreover our findings confirm the harmful effects of anti-class I DS-Abs on long-term graft survival.
Antibody Formation↗
HLA class I residue mismatch and renal graft outcome.
Donor-recipient HLA matching was retrospectively evaluated in 111 cadaveric renal transplants using Takemoto's ten-residue model in which HLA class I antigens are clustered by crossreactive group (CREGs) on the basis of amino acid sequence homology and the sharing of a particular public epitope. The grade and type of HLA residue mismatching were correlated to posttransplant, class I donor-specific antibody production (monitored by flow cytometry crossmatch), rejection occurrence and clinical outcome during the 1st year posttransplant. In 52 patients with 0 mismatchings (MMs) we observed a low incidence of rejection (11.1%) and antibody production (11.1%) for 0 CREG MM grade, while 1 MM was enough to increase immune response against graft (rejection 35%; antibodies 30%). Moreover, a significant correlation was observed between Q144, E163, Q62 and L82/R82 epitopes and the incidence of acute rejection and antibody production ("immunogenic" residues) in patients grouped for a single residue mismatch.
Antibody Formation↗
Simultaneous measurement of soluble carcinoembryonic antigen and the tissue inhibitor of metalloproteinase TIMP1 serum levels for use as markers of pre-invasive to invasive colorectal cancer.
Matrix metalloproteinases (MMP) are members of a multigene family of zinc-dependent enzymes involved in the degradation of extracellular matrix components. Cancer research suggest that MMP and tissue inhibitors of metalloproteinases (TIMP) may be involved in disease progression; these enzymes could therefore be used as markers in cancer prevention programmes and for clinical monitoring. To establish whether MMP and TIMP can be used effectively as markers we determined serum levels of MMP1 and TIMP1, and studied the relationships between these enzymes and the stage of disease. The potential diagnostic and prognostic value of serum level measurements of MMP1 and TIMP1 was evaluated by comparing them with serum levels of soluble carcinoembryonic antigens (sCEA) and p53 antibodies. Our overall results indicate that simultaneous measurements of serum sCEA and TIMP1 in patients with colorectal cancer could be used as prognostic and diagnostic markers for disease progression from the pre-invasive nodal phase to the invasive phase (stages I, II to III, IV). In addition, serum levels of TIMP1 could be used as a selective marker for metastatic disease (stage III to IV). In fact, the 95% confidence interval of the serum levels of sCEA at stage III (18.4 < or = sCEA < or = 68.6 ng/ml) and TIMP1 at stage IV (1620 < or = TIMP1 < or = 3906 ng/ml) identified statistically significant ranges of values (sCEA P = 0.02, TIMP1 P = 0.02), which may be useful in the monitoring of patients at these disease phases. More specifically, our data suggest that, when the serum level of sCEA is below 18.4 ng/ml and the level of TIMP1 below 1620 ng/ml, there is a 95% probability that the disease is in the pre-invasive nodal phase; when the serum level of sCEA falls between 18.4 ng/ml and 68.6 ng/ml and the level of TIMP1 is below 1620 ng/ml, there is a 95% probability that the disease is in the phase when lymph node infiltration occurs; when the level of sCEA is above 68.6 ng/ml and the level of TIMP1 is at least 1620 ng/ml, there is a 95% probability that the disease is in the metastatic phase.
Adult↗
Sequence analysis of a new HLA-DR11 allele in a Caucasian Italian family: DRB1*11272.
This communication describes a new DRB1*11 allele identified in a familial group of Caucasian individuals from central Italy. The new sequence has been officially named DRB1*11272 by the World Health Organization (WHO) Nomenclature Committee (February 2000). It encodes an HLA antigen serologically recognized as DR11. The sequence variation of this new allele was localized to codon 77 of exon 2. It differs at position 230 from DRB1*11011 allele (A replacing C), and at position 231 from DRB1*1127 (C replacing T). At the amino acid level, the DRB1*11272 mutation is silent with respect to the DRB*1127 phenotype, coding for a synonymous asparagine.
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The TH1 and TH2 cytokine network in healthy subjects: suggestions for experimental studies to create prognostic and diagnostic indices for biotherapeutic treatments.
In vivo and in vitro studies have demonstrated the selective regulatory effect that TH1 and TH2 cytokines reciprocally exert in the regulation of the polarization of precursor cells into TH1 or TH2 types. The study of the network relationships between TH1 and TH2 (TH1/TH2) cytokines in healthy subjects could lead to a better understanding of how the physiological network of cytokines regulates the immune response. Such study could lead to gain suggestions for follow-up experiments to create prognostic and diagnostic indices for biotherapeutic treatments of patients. Hence we determined serum levels (environment network) and PBMC production (cellular network) of IL2, IFN gamma, IL4, IL6 and IL10 in the peripheral blood of healthy subjects; these cytokines made up our networks under basic conditions. Both men and women were studied as hormones can influence the polarization of TH1 and TH2 cells. Cytokines within the physiological network function simultaneously so multivariate statistical methods were used to study TH1/TH2 relationships. The use of mathematical modelling is the only effective way of studying the immune system as a whole. The physiological TH1/TH2 network under activation conditions was evaluated by incorporating: sIL2R and sIL6R into the basic environment network model and the production levels of cytokines by PBMC after PHA stimulus, into the basic cellular network model. The influence of APC was evaluated by adding: serum levels of TNF alpha and IL1 beta to the environment network model, and production levels of IFN gamma, IL10 and IL6, after stimulus with LPS, to the cellular network model. Our results led us to hypothesize that the physiological network of TH1/TH2 cytokines regulates TH polarization by means of specific relationships between TH1 and TH2 cytokines, which may be different in men and women. These relationships could be studied experimentally to create prognostic and diagnostic indices for more efficient prevention programs and biotherapeutic treatments of patients.
Adult↗
[Tissue-typing laboratories for organ transplantation].
The tissue typing laboratory performs genetic analysis: the safety and the reproducibility of results are mandatory, because HLA typing can be crucial both in donor-recipient compatibility assessment for organ transplantation and for the diagnosis of immune related disease. The HLA laboratory should perform analysis, as quickly as possible, in order to define donor-recipient matching and to assess the presence of anti-donor specific antibodies in recipient's serum to prevent iperacute rejection. The aim of this report is to define the guidelines that should be followed in all laboratories for each specific transplantation in order to acquire national and international accreditation, and to obtain the best clinical results.
Histocompatibility Testing↗