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P A Dyer

Publications and source records attributed to P A Dyer.

At least 19 recordsLinked to original sources
PubMed1996

Importance of minimizing HLA-DR mismatch and cold preservation time in cadaveric renal transplantation.

Univariate and multivariate analyses have been performed on donor an d recipient variables to determine possible effects on the outcome of 516 primary cadaveric renal transplants performed in our single center from 1989 until 1993. The overall actuarial patient survival at 1 year and 5 years was 94.4% and 87.4%, respectively; the 1 year and 5 year graft survival rates were 88.3% and 77.8%, respectively. A total of 95 grafts were lost; death with function (35%) and chronic rejection (22%) were the major causes. Three variables (HLA-DR mismatch, delayed graft function, and prolonged cold ischemia time) had a significant detrimental effect on both short- and long-term graft survival. Zero HLA-DR mismatched grafts showed significantly enhanced survival over those with 1 HLA-DR mismatch both at 1 year (92.8% vs. 84.5%) and at 5 years (88.3% vs. 73.9%) only if cold ischemia time was less than 26 hours (P=0.0009). Occurrence of delayed graft function significantly lowered graft survival at both 1 year and 5 years (P=0.002), and the incidence was significantly associated with prolonged cold ischemia time (P<0.0001). HLA-A or HLA-B matching, percentage panel reactive antibodies (PRA), and anastomosis time showed no independent effect on long-term survival. The small number of 2 HLA-DR mismatched grafts (n=6) precluded separate analysis of this group. Acute rejection accounted for 12% of losses but had no statistically significant effect on graft survival, even though an increased frequency of rejection episodes was significantly associated with HLA-DR mismatch (P<0.0001). These results would suggest that significant survival benefits may be achieved by prospective HLA matching if cold ischemia times are limited. The efficiency of organ sharing must he improved to make optimal use of a limited resource.

Adolescent↗
PubMed1996

Polymyalgia rheumatica is associated with both HLA-DRB1*0401 and DRB1*0404.

The frequency of HLA-DRB1 alleles was determined in 68 Caucasoid patients with polymyalgia rheumatica (PMR) and 140 controls using polymerase chain reaction (PCR) sequence-specific oligonucleotide typing. In keeping with previous studies, an increased frequency of DRB1*04 was observed in patients [55.9% vs 35.0%, odds ratio (OR) 2.4, 95% confidence interval (CI) 1.3-4.4]. HLA-DRB1*0101 frequency was also increased in patients, although less confidence could be placed on this association (19.1% vs 14.3%, OR 1.4, 95% CI 0.6-3.3). HLA-DRB1*04 subtyping indicated that the frequencies of both DRB1*0401 (38.2% vs 22.1%, OR 2.2, 95% CI 1.0-4.3) and DRB1*0404 (16.2% vs 5.0%, OR 3.7, 95% CI 1.2-11.1) were specifically raised. An increased frequency of the RA shared epitope (QKRAA/QRRAA) was also observed in this group (75.0% vs 44.2%, OR 3.8, 95% CI 1.9-7.6). When the analysis was restricted to only DRB1*04-negative patients and controls, the frequencies of DRB1*0301, *11 and *08 were marginally raised. However, no obvious relationship appeared to exist between PMR susceptibility and DRB1 alleles carrying the DYF conserved epitope in the second hypervariable region. Autoantibodies to thyroid antigens were present in 23% of patients. An increased frequency of DRB1*0301 was observed in patients with thyroid microsomal antibodies compared to those without (54.5% vs 24.6%, OR 3.7, 95% CI 0.8-17.0). This increase was not observed in patients with thyroglobulin autoantibodies. These data indicate that both DRB1*0401 and *0404 are associated with PMR, and that this may extend to include DRB1*0101. The immunogenetic profile of susceptibility markers in this condition appears to be similar to that in rheumatoid arthritis.

Aged↗
PubMed1996

Immunogenetic factors in HPV-associated cervical cancer: influence on disease progression.

No HLA allele or specificity was significantly different in frequency between a group of 150 cervical cancer patients from north-west England and controls (corrected P values). HLA-DRB1*1501/DQB1*0602 was non-significantly increased, particularly among patients with HPV16-positive tumours. HLA-B7-positive patients had a significantly poorer clinical outcome than HLA-B7-negative patients. A significant component of the genotypic effect is down-regulation of HLA-B7 expression by the tumour cells.

Adult↗
PubMed1996

Outcome of pediatric cadaveric renal transplantation: a 10 year study.

This report deals with 120 cadaveric renal transplants performed in 101 pediatric recipients in this Centre in two five-year periods, 1984 to 1988 (N = 65) and 1989 to 1993 (N = 55). In the first group transplants were allocated on the basis of best size (small donors for small recipients); in the second group priority was given to beneficial HLA matching. Initial immunosuppression was either cyclosporine (CsA) monotherapy (15 mg/kg/day), or triple therapy (CsA 5 mg/kg/day, prednisolone 1 mg/kg/day and azathioprine 1 mg/kg/day) if there was delayed graft function. Patient survival at one year and five years (97.5% and 92.3%, respectively) did not differ between the two groups, although there was an improvement in graft survival at one and five years in the second period relative to the first: 69.2% and 53.8% versus 78.6% and 65.6%. This did not achieve statistical significance. One year graft survival in recipients under five years did not differ significantly from older children (72%). There was a trend to improvement in one year graft survival in the < five years of age pediatric patients in Group 2, with beneficially matched kidneys and improved immunosuppressive management. Graft losses due to acute rejection were similar in both groups. Donor age < 4 years significantly reduced one year graft survival (63% vs. 85%, P = 0.01), while recipient age had no effect. Small donor kidneys were associated with a higher incidence of graft thrombosis. Transplantation resulted in the normalization or acceleration of growth velocity in (84%) of the pre-pubertal children who completed follow up. In conclusion, we have shown that excellent patient and graft survival can be achieved in children transplanted under the age of five years. Kidneys from donors under the age of four years are associated with an unacceptable rate of graft loss. Small children do not readily accept cyclosporine monotherapy. Successful early renal transplantation offers the best chance of normal growth and development.

Adolescent↗
PubMed1995

A genetic marker of high TNF-alpha production in heart transplant recipients.

The cytokine TNF-alpha has been implicated in the pathogenesis of both acute and chronic transplant rejection. Levels of the cytokine are known to vary in a normal population, leading to speculation that high responders may be at greater risk of rejection. Particular TNF region polymorphic markers have been associated with increased TNF-alpha levels and a biallelic polymorphism has been identified at position -308 of the TNF-alpha promoter that may contribute significantly to the interindividual variation in healthy persons. We describe here a new association between a polymorphic locus in the TNF gene region and increased production of TNF-alpha in heart transplant recipients. We studied two microsatellite markers that flank the TNFA gene, as well as a biallelic polymorphism at position -308 of the TNFA promoter, and found that the microsatellite allele TNFd3 was significantly associated with the capacity of leukocytes to produce TNF-alpha in vitro. No association was demonstrated for the promoter region polymorphism. Patients were receiving cyclosporine (CsA) and prednisolone (pred) at the time of sampling, which are known to interrupt 5' regulation of TNFA transcription in T cells and macrophages and may therefore negate the influence of the -308 polymorphism. Because of this we suggest that TNFd3 may be a marker for a 3' repressor region polymorphism that is of importance in immunosuppressed individuals.

Alleles↗
PubMed1995

Frequency of down-regulation of individual HLA-A and -B alleles in cervical carcinomas in relation to TAP-1 expression.

The development of cervical carcinoma is strongly associated with specific types of human papillomaviruses (HPVs). A role for cellular immunity in cervical disease is supported by the increased occurrence of HPV-associated lesions in immunosuppressed individuals. Upon viral infection or malignant transformation, ensuing alterations in gene expression result in the generation of novel sets of peptides which can form complexes with specific HLA class I heavy chains and beta 2-microglobulin. These are then expressed at the cell surface as potential targets for specific T cells. In this study of 100 carcinomas HLA-A and -B class I expression by the tumour cells was down-regulated at one or more alleles in at least 73% of cervical carcinomas. Interference with the transporter associated with antigen presentation (TAP), which translocates cytosolic peptides from endogenously synthesised proteins (e.g. viral) into the lumen of the endoplasmic reticulum was found in 38% of the HLA class I down-regulated tumours. Loss of expression for common HLA class I alleles ranged from 36% to 71%, and such changes might be expected to influence specific immunogenic peptide presentation and consequent immune recognition. These results underline the importance of single as well as multiple allelic loss in cervical neoplasia and have important implications for attempts to intervene immunologically in cervical cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Histocompatibility testing for kidney transplantation: an update.

Histocompatibility testing prior to kidney transplantation is an established necessity. Recipient sensitization to HLA specificities affects the efficacy of the lymphocytotoxic cross-match and influences the achievable HLA mismatch. Within Europe most cadaver donor kidneys are allocated on the basis of minimum histocompatibility mismatch contrasting with the North American system which allows for exchange of kidneys only where there is no detectable donor/recipient mismatch. There is also a contrast between the immunosuppression protocols used in these continents with, in general, more aggressive regimens used in North America. In the 1990s there has been considerable refinement in the techniques available to histocompatibility laboratories for definition of HLA phenotypes and genotypes and some obstacles to successful transplantation have been overcome. We review some of these changes with particular reference to our own experience.

Antibodies↗
PubMed1995

Definition of HLA-C alleles using sequence-specific oligonucleotide probes (PCR-SSOP).

Many new HLA-C locus alleles have recently been identified by DNA sequencing, and a molecular based method for their detection using PCR with sequence specific primers has been reported. However, other methods may be more appropriate for the identification of C locus alleles in larger studies. Here we describe one such system, based on PCR sequence specific oligonucleotide probes, (SSOP) for C locus typing. Advantages of SSOP typing compared to SSP are that it is easier to detect new alleles, more cost effective and less time consuming. We have developed a DNA typing method to identify the broad C locus antigens (including those not yet defined serologically) using a minimum of probes with one amplification. We use a C locus specific sense primer in exon 2 and a consensus antisense primer in exon 3, in a two-step PCR, giving a product of 710 bp. Probes were designed with similar melting temperatures (54-56 degrees C) that would identify as many alleles as possible. The method was established using DNA from B lymphoid cell lines of known C locus type, mostly 10th workshop homozygous cell lines, plus as many other sequenced cell lines as possible. The system was able to correctly identify their C locus types using only 26 probes. DNA was tested from a panel of serologically typed individuals which included many different heterozygous combinations. We found a high concordance of results, with all discrepancies being additional antigens identified by molecular typing, filling in serological blanks. We can identify all common heterozygote combinations using this method.

Alleles↗
PubMed1995

Lack of influence of non-inherited maternal HLA-DR alleles on susceptibility to rheumatoid arthritis.

OBJECTIVE: To reproduce findings from previous reports that non-inherited maternal HLA class II antigens might contribute to rheumatoid arthritis (RA) susceptibility in the offspring. METHODS: Families were recruited from the Arthritis and Rheumatism Council's National Repository of RA families and HLA-DRB1 alleles were examined in these individuals and their first degree relatives using DNA typing methods. RESULTS: There was no evidence of an increase in either non-inherited maternal HLA-DR4 or the HLA-DRB1 shared epitope as a whole compared with the frequency expected using the non-inherited paternal antigens as controls. CONCLUSIONS: The numbers of probands who were shared epitope negative were small, but we are unable to confirm in these families the findings that non-inherited maternal HLA contributes an additional susceptibility factor to rheumatoid arthritis.

Alleles↗
PubMed1994

Rejection in heart transplantation strongly correlates with HLA-DR antigen mismatch.

It is well established that incompatible HLA antigens presented by donor tissue readily evoke an immune response. Prospective HLA matching policies, widespread in European kidney transplant centers have reduced the level of HLA mismatching and have significantly improved graft survival. The influence of HLA incompatibility in heart transplantation remains controversial, and prospective HLA matching is seldom achieved. We examined the role of HLA antigen mismatching on transplant rejection by analyzing 2569 endomyocardial biopsies (EMB) from 157 consecutive orthotopic heart transplants performed from April 1987 to August 1993 in our own center. Biopsies were graded according to the accepted International Classification, with grade 2 and higher indicating rejection. Among 91 patients who received a 2 HLA-DR mismatch transplant 34% of 1624 biopsies analyzed were graded as > or = 2. This frequency fell to 29% of 797 biopsies for 53 patients with a one-HLA-DR mismatch and to 18% of 148 biopsies for 13 patients in the zero-HLA-DR-mismatch group (P < 0.00005). No significant effect on EMB grade frequencies was observed using the same method of analysis with transplants mismatched at the HLA-A or HLA-B loci apart from analysis of HLA-B matched transplants at 3 months posttransplant (P = 0.02). The close linkage of the HLA-B and HLA-DR loci may account for this observation. The results of this study show that heart transplants matched at the HLA-DR locus have a significantly reduced incidence of EMB grades indicative of rejection requiring augmented immunosuppressive therapy. We propose that prospective HLA-DR matching should be adopted for allocation of donor hearts for more efficient use of this precious and limited resource.

Adolescent↗
PubMed1994

"Homozygosity" for the HLA-DR shared epitope contributes the highest risk for rheumatoid arthritis concordance in identical twins.

OBJECTIVE: To assess the contribution of HLA-DRB1 alleles in determining rheumatoid arthritis (RA) concordance in monozygotic twins. METHODS: Ninety-one monozygotic twins pairs in which at least 1 twin was affected were typed for HLA-DRB1 using both serologic methods and polymerase chain reaction amplification with sequence-specific oligonucleotide hybridization. The role of DR4 and of the shared epitope in disease concordance was investigated. Relative risks (RR) with 95% confidence intervals were determined. RESULTS: Increased concordance for RA was observed in both DR4 positive and shared epitope positive pairs (RR 3.4 and 3.7, respectively). A 5-fold risk for RA concordance was seen in twins who were "homozygous" for the shared epitope, compared with those negative for the shared epitope. CONCLUSION: In the absence of the shared epitope, RA concordance in monozygotic twins is rare. In contrast, "homozygosity" for the shared epitope is the most important factor in determining RA concordance.

Arthritis, Rheumatoid↗
PubMed1994

Do specific HLA antigens predispose to ischaemic heart disease or idiopathic dilated cardiomyopathy?

BACKGROUND: The aetiology of idiopathic dilated cardiomyopathy is believed to have an immunological component. Association with human leucocyte antigens (HLAs) has been previously reported, particularly with HLA-DR4. AIM: To determine the association of HLA type with diagnosis in a group of patients assessed for heart transplantation. METHODS: A comparison was made of frequencies of HLA types in patients with a diagnosis of idiopathic dilated cardiomyopathy or (n = 98) ischaemic heart disease (n = 170) and in controls from the North Western region (n = 857). RESULTS: Neither the patients with idiopathic dilated cardiomyopathy nor those with ischaemic heart disease showed a significant increase or decrease in any HLA frequency compared with the controls. CONCLUSION: These results suggest that there is no HLA association with idiopathic dilated cardiomyopathy or ischaemic heart disease. This conflicts with the results of some previous studies.

Cardiomyopathy, Dilated↗
PubMed1993

HLA mismatching and cytomegalovirus infection as risk factors for transplant failure in cyclosporin-treated renal allograft recipients.

In a study of the effects on renal allograft survival of HLA mismatching, mismatching for cytomegalovirus (CMV) antibody status, and post-transplant CMV infection, 148 cyclosporin-treated renal transplant recipients were given kidneys optimally matched for HLA-A, -B, and -DR antigens but not matched for CMV antibody status. Mismatching for HLA-B and -DR antigens was associated with a greater number of rejection episodes and a lower graft survival, but mismatching for CMV antibody status and posttransplant primary or recurrent CMV infection exerted no effect on graft survival. The role of matching of renal transplant recipients and donors for CMV antibody status in preference to HLA matching (proposed as a means of reducing the mortality associated with primary CMV infection) is discussed.

Antibodies, Viral↗
PubMed1993

Lack of association of HLA polymorphisms with human papillomavirus-related cervical cancer.

An association of HLA-DQ3 with SCC of the cervix has been reported by researchers in Germany and Norway. This article documents a similar-sized study with patients and controls from northwest England. We report in detail on serologically determined HLA polymorphism in SCC patients with respect to HPV 16 infection, MHC class II expression within the tumor, serologic response to HPV, and other relevant clinical variables. We have also extended our studies to include DNA-based analysis using PCR and SSO probes for HLA-DQ. No significant association of any HLA-A, -B, -C, -DR, or -DQ antigen with SCC patients was found. While a possible explanation of the differences among studies could be a reflection of disease heterogeneity, the several tumor and clinical factors examined do not account for the observed differences from previous reports. Further studies are needed for a greater understanding of the interaction of HPV and HLA type in the development of cervical neoplasia.

Adult↗