Biomedical subjects

B D Tait

Publications and source records attributed to B D Tait.

At least 19 recordsLinked to original sources

PubMed2005

Clinical, laboratory and genetic markers associated with erosions and remission in patients with early inflammatory arthritis: a prospective cohort study.

We investigated the relationship between clinical, laboratory and genetic markers and outcome measures in 159 patients with recent onset of inflammatory arthritis (IA). The majority of patients were managed in community-based rheumatology practice. Median duration of arthritis at baseline was 3 months with median follow-up of 4.0 years (range 0-10). Markers of disease activity and 1987 ACR criteria for rheumatoid arthritis (RA) were estimated every 6 months for the first 2 years and annually thereafter. Presence of shared epitopes (SE) was established by PCR-based method. Main outcome variables were attainment of remission and presence of erosions on X-rays of hands and feet at 3 years. Remission was seen in 34.3% of patients and was independently related to age 60 and older (odds ratio (OR) 3.2; 95% confidence interval (CI), 1.2-8.7) and inversely to the presence of rheumatoid factor (RF) (OR 8.3; 95% CI, 3.2-21.3 for persistent arthritis). Patients with two SE were likely to have persistent arthritis (P=0.006), but this was not significant when corrected for RF. Independent predictors for erosions at 3 years were RF (OR 7.5; 95% CI, 1.9-29.5) and area under the curve for number of swollen joints (OR 1.08; 95% CI, 1.02-1.16). SE status was not predictive of erosions at 3 years (OR 1.6; 95% CI, 0.7-3.7). In univariate analysis, patients possessing DERAA motif on DRB1 were less likely to have erosive disease than without this motif at 4 years (OR 0.21; 95% CI, 0.0-0.9, P=0.037) but this finding was partly explained by adjusting for RF (adjusted OR 0.24; 95% CI 0.04-1.37). In this study of recent onset IA, active disease and RF were associated with poor outcome. Whilst SE did not predict erosive disease, patients with DERAA motif may be protected against erosions whilst the presence of two SE alleles suggests persistence of arthritis.

Age of Onset↗

PubMed2003

HLA genes associated with autoimmunity and progression to disease in type 1 diabetes.

Insulin dependent diabetes mellitus (type I DM) is caused by an autoimmune process which culminates in destruction of pancreatic beta cells with resultant loss of insulin production. Preceding the clinical diagnosis of type I DM is a preclinical stage characterized by autoantibodies to insulin, glutamic acid decarboxylase (GAD) and a tyrosine phosphatase-like molecule (IA-2). We have studied both HLA class I and class 2 allele distributions in diabetic probands and autoantibody positive individuals in members of 452 families recruited for the Australian type I diabetes DNA repository. The results demonstrate that progression to autoimmunity as measured by the appearance of autoantibodies is strongly associated with the class 2 alleles DRB1*03 and DRB*04 and with DRB1*03/04 heterozygosity. In contrast, the progression to clinical disease appears associated with class I alleles A24, A30 and B18 while A1, A28, B14 and B56 appear negatively associated. The class 2 alleles appear to have a minimal role in the progression from autoantibody positivity to clinical disease. These results are consistent with the view that CD4+ T cells responding to peptides in the context of class 2 molecules are responsible for initiating autoantibody production, while the destruction of islet cells leading to clinical expression of the disease is the function of CD8+ T cells recognizing relevant peptides in the context of class I molecules.

Alleles↗

PubMed2002

CCR5 genotyping in an Australian and New Zealand type 1 diabetes cohort.

Infiltration of pancreatic tissue by autoreactive T-cells involves secretion of multiple cytokines and chemokine receptor expression. Genetically determined variation in cell surface expression of the chemokine receptor CCR5 may result in differences in inflammatory cell migration in response to relevant chemokines. Adolescents with type 1 diabetes (T1D) from Australia and New Zealand were genotyped for CCR5-delta32 (n = 626). The allele frequency was compared with that of 253 non-diabetic Australian adolescents and with that of 92 adults with systemic lupus erythematosus. A reduced allele frequency was seen in T1D compared with controls (0.092 vs. 0.123, p = 0.05). This difference was not seen for the cohort of patients with SLE (freq = 0.114). A reduction in the number of CCR5-delta32/delta32 homozygotes, who lack CCR5, in the T1D cohort was also seen and while not statistically significant (2 observed compared to 5.25 expected; p = 0.12) is interesting. These results suggest a partial protection from T1D for CCR5-delta32 homozygous individuals is possible and that CCR5 has a potential role in the pathogenesis of T1D.

Adolescent↗

PubMed2001

4-Hydroxy-5,6-dihydropyrones as inhibitors of HIV protease: the effect of heterocyclic substituents at C-6 on antiviral potency and pharmacokinetic parameters.

Due largely to the emergence of multi-drug-resistant HIV strains, the development of new HIV protease inhibitors remains a high priority for the pharmaceutical industry. Toward this end, we previously identified a 4-hydroxy-5,6-dihydropyrone lead compound (CI-1029, 1) which possesses excellent activity against the protease enzyme, good antiviral efficacy in cellular assays, and promising bioavailability in several animal species. The search for a suitable back-up candidate centered on the replacement of the aniline moiety at C-6 with an appropriately substituted heterocyle. In general, this series of heterocyclic inhibitors displayed good activity (in both enzymatic and cellular tests) and low cellular toxicity; furthermore, several analogues exhibited improved pharmacokinetic parameters in animal models. The compound with the best combination of high potency, low toxicity, and favorable bioavailabilty was (S)-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (13-(S)). This thiophene derivative also exhibited excellent antiviral efficacy against mutant HIV protease and resistant HIV strains. For these reasons, compound 13-(S) was chosen for further preclinical evaluation.

Animals↗

PubMed2001

Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele.

Type 1 diabetes (T1D; or insulin-dependent diabetes mellitus, IDDM) is an autoimmune disease with both genetic and environmental components. In addition to the human leukocyte antigen (HLA) complex, the single major genetic contributor of susceptibility, an unknown number of other unidentified genes are required to mediate disease. Although many loci conferring susceptibility to T1D have been mapped, their identification has proven problematic due to the complex nature of this disease. Our strategy for finding T1D susceptibility genes has been to test for human homologues of loci implicated in diabetes-prone NOD (non-obese diabetic) mice, together with application of biologically relevant stratification methods. We report here a new susceptibility locus, IDDM18, located near the interleukin-12 (IL-12)p40 gene, IL12B. Significant bias in transmission of IL12B alleles was observed in affected sibpairs and was confirmed in an independent cohort of simplex families. A single base change in the 3' UTR showed strong linkage disequilibrium with the T1D susceptibility locus. The IL12B 3' UTR alleles showed different levels of expression in cell lines. Variation in IL-12p40 production may influence T-cell responses crucial for either mediating or protecting against this and other autoimmune diseases.

3' Untranslated Regions↗

PubMed2000

5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities: potent nonpeptidic inhibitors of HIV protease.

On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S(3)' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S(3)' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1. In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.

Animals↗

PubMed2000

HLA class I expression on human cancer cells. Implications for effective immunotherapy.

Early studies demonstrated the role of cytotoxic T cells as an immune defence mechanism against tumour cells. The demonstration of tumour antigen peptides and their presentation to T cells on major histocompatibility complex class I molecules highlighted the importance of these molecules in effective anti-tumour responses. It is well established that many tumours escape T cell recognition by loss or down regulation of class I molecule expression on the cell surface of tumour cells. Tumours which have lost class I expression are immunoselected and as a result have a propensity for growth and metastatic spread. With the development of cancer vaccine strategies for clinical use, there will be a future role for histocompatibility laboratories in determining class I expression on tumour cells in individual patients. These studies of expression will require not just the demonstration of total class I expression but the demonstration of locus and allele specific class I molecules involved in the relevant tumour peptide presentation. These studies will be pivotal in tailoring individual patient therapies. The identification of appropriate monoclonal antibody reagents for class I expression and techniques used on different kinds of tissue sections will be a component of the forthcoming 13th International Histocompatibility Workshop.

Animals↗

PubMed2000

Identification of a novel DPB1* allele (DPB1*6901) and the occurrence of HLA haplotypes that extend to DPB1.

The sequence of a novel DPB1 allele, DPB1*6901, observed in a Caucasian bone marrow donor phenotype HLA A2; Cw*0501,*1601; B*4402, *4403; DRB1*0401; *07; DQB1*02; *0301; DPB1*0401; *6901, is described. The sequence is consistent with that previously described for DPB1*0601 with the exception of codon 69. The sequence at this codon is consistent with that previously observed only in the DPB1*1101 and *1501 alleles. It is suggested that DPB1*6901 may have arisen as a result of a recombination event occurring between codons 58 and 64 between DPB1*0601 and DPB1*1101. The sequence of DPB1*1501 from codon 64 is not consistent with DPB1*6901. A linkage disequilibria analysis that examined 212 potential bone marrow recipients in which HLA-A to DQ haplotypes had been established by family studies showed linkage disequilibrium between HLA-B, DRB1 and DPB1 in some haplotypes and not others.

Alleles↗

PubMed2000

Screening for preclinical type 1 diabetes in a discrete population with an apparent increased disease incidence.

Environmental agents are proposed to play a role in triggering or exacerbating pancreatic islet autoimmunity in people genetically predisposed to type 1 diabetes. However, with few exceptions, these agents remain enigmatic. Clues to environmental agents may be found by investigating population/geographic clusters or 'hotspots' of high disease incidence. We were alerted to a small community where the incidence of type 1 diabetes appeared to be five-fold higher than expected. Because type 1 diabetes is now recognized to have a subclinical phase during which anti-islet antibodies can be detected, we aimed to identify and characterize a reservoir of children with subclinical disease in this community. Venous blood samples were collected from 1906/2347 (81%) local school children during one week. Islet cell antibodies (ICAs) were detected in 122 (6.4%) children, 18 (0.9%) being high titer (> or = 20 Juvenile Diabetes Foundation units (JDFu)). On retest, 15 months later, the majority of low titer ICAs were undetectable, whereas high-titer ICAs persisted. The latter were found in two distinct age-related, ethnically similar groups. The younger group, aged 6-9 yr, had antibodies to insulin (IAAs), glutamic acid decarboxylase (GAD) and tyrosine phosphatase IA2 in addition to ICA, human leukocyte antigen (HLA) genes associated with susceptibility to type 1 diabetes, and lower first-phase insulin responses (FPIRs) to intravenous glucose. The older group, aged 13-16 yr, the age cohort of the index clinical cases, had few antibodies other than ICA, non-susceptibility HLA genes and normal FPIRs. During follow-up, three children, all from the younger group with multiple antibodies and FPIRs less than the first percentile, developed diabetes 4, 6 and 7 yr after screening. The finding of two age groups of subclinical disease suggests that if environmental agents triggered islet autoimmunity they did not act constantly on the community. Furthermore, the absence of multiple autoantibodies and/or HLA susceptibility genes in the older group, the source of index clinical cases, implies they are a residual subgroup with slow or absent progressive beta-cell destruction. This study illustrates that the natural history of type 1 diabetes may be elucidated by analyzing age-related subclinical disease in the general population.

Journal Article↗

PubMed2000

Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes.

Pancreatic islet autoimmunity leading to type 1 diabetes could be triggered by viruses in genetically susceptible individuals. Rotavirus (RV), the most common cause of childhood gastroenteritis, contains peptide sequences highly similar to T-cell epitopes in the islet autoantigens GAD and tyrosine phosphatase IA-2 (IA-2), suggesting T-cells to RV could trigger islet autoimmunity by molecular mimicry. We therefore sought an association between RV infection and islet autoantibody markers in children at risk for diabetes who were followed from birth. There was a specific and highly significant association between RV seroconversion and increases in any of these antibodies: 86% of antibodies to IA-2, 62% to insulin, and 50% to GAD first appeared or increased with increases in RV IgG or IgA. RV infection may therefore trigger or exacerbate islet autoimmunity in genetically susceptible children.

Antigens, Viral↗

PubMed1999

Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing a novel and achiral 3-(2-t-butyl-5-methyl-4-sulfamate)phenylthio moiety.

Dihydropyran-2-ones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were designed to reach S3' pocket of the HIV protease. Synthetic routes for the preparation of thiotosylates possessing 3-(2-t-butyl-5-methyl-4-sulfamate) phenylthio moiety were established. SAR of various sulfamate analogs including HIV protease binding affinities, antiviral activities and therapeutic indices will be described.

Animals↗

PubMed1999

Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing achiral 3-(4-amino/carboxamide-2-t-butyl,5-methylphenyl thio) moiety: antiviral activities and pharmacokinetic properties.

Dihydropyran-2-ones possessing amino and carboxamide functionalities on 3-SPh (2-tert-butyl, 5-methyl) ring were synthesized and evaluated for their antiviral activities. Both the enantiomers of inhibitor 15 were synthesized. The in vitro resistance profile, inhibitory activities against cytochrome P450 isozymes and pharmacokinetic properties of inhibitor 15S will be discussed.

Animals↗

PubMed1999

Antibodies to type II collagen and HLA disease susceptibility markers in rheumatoid arthritis.

OBJECTIVE: To seek associations between antibodies to native and denatured type II collagen (NCII and DCII) and HLA in rheumatoid arthritis (RA). METHODS: One hundred fourteen patients with clinically well-defined RA were HLA-DR and DQ typed. Those who were DR4 positive were subtyped for DRB1*0401-*0408 alleles by polymerase chain reaction using allele-specific oligonucleotide probes. Antibodies to human NCII and DCII (heat-denatured) were measured by enzyme-linked immunosorbent assay. The frequency of HLA alleles was compared in patients grouped according to the presence and absence of antibodies to NCII and DCII. RESULTS: Twenty-seven patients (24%) were positive for antibodies to NCII. There was a significant increase in the frequency of HLA-DR7 in anti-NCII-positive patients compared with anti-NCII-negative patients (30% versus 9%; P = 0.019) and a significant decrease in HLA-DR3 (7% versus 28%; P = 0.044). Repeating the analyses after excluding the 16 patients who were DR7 positive revealed a significant increase in the frequency of HLA-DR1 in anti-NCII-positive patients compared with anti-NCII-negative patients (63% versus 27%; P = 0.045). Moreover, antibodies to NCII were associated with the third hypervariability region susceptibility sequence QRRAA that is present in DRB1*0101, *0404, *0405, and *0408 (84% versus 47%; P = 0.0085); 24 of 27 anti-NCII-positive patients were positive for either DR7, DR1, or DRB1*0404 or *0408. Thirty patients (26%) were positive for antibodies to DCII. There was a significant increase in the frequency of HLA-DR3 in anti-DCII-positive patients compared with anti-DCII-negative patients (40% versus 18%; P = 0.028). CONCLUSION: The genetic associations between HLA-DR alleles and antibodies to CII in RA patients is in keeping with the collagen-induced arthritis model and implicates autoimmunity to CII as a major component in the multifactorial pathogenesis of RA.

Alleles↗

PubMed1999

Matching for HLA DPA1 and DPB1 alleles in unrelated bone marrow transplantation.

The impact of donor-recipient DPA1 and DPB1 matching was examined in 122 unrelated bone marrow transplant pairs. All pairs were serologically matched at the time of transplantation for HLA class I and II and a majority also DRB1 allele matched. Retrospective A, B, C, DRB1, DQA1, DQB1 in addition to DPA1 and DPB1 allele matching was performed by molecular techniques. The percentage of pairs that were allele matched was as follows; HLA-A = 91% (n = 80), HLA-B = 94% (n = 80), HLA-C = 78% (n = 80), HLA-DRB1 = 96% (n = 122), HLA-DQA1 = 99% (n = 80), HLA-DQB1 = 92% (n = 122). 92 recipient/donor pairs with informative clinical data were available for analysis. DPA1 identity (no incompatibility in either direction) was observed in 57% and DPA1 compatibility in 76% of pairs with no apparent beneficial effect of matching on patient survival or Graft Versus Host Disease (GVHD). DPB1 identity was observed in 11% and compatibility in 27% of pairs. A significant improvement in patient survival was observed in DPB1 matched compared to one DPB1 mismatch (p < 0.01) and combined one and two DPB1 mismatched transplants (p = 0.03). This beneficial effect remained when allele mismatches at HLA-A, B, C, DRB1, DQA1, DQB1 were excluded (p = 0.05, p = 0.03, respectively). There was a significant association of increased frequency of severe GVHD (grades III-IV) compared to mild GVHD (grades I-II) with DPB1 mismatched transplants compared to DPB1 matched transplants (p = 0.04). In DPB1 mismatched transplants an association between patient survival and matching for individual DPB1 polymorphic regions was not observed; however in the HLA-A, B, DRB1, DQA1, DQB1 allele matched transplants a non significant increase in the frequency of Grade IV GVHD was observed in recipients who were negative compared to those who were positive for DPB1 alleles coding for glutamic acid at position 69.

Adult↗

PubMed1999

Polymorphism in the regulatory regions of the HLA-DPB1 gene.

Nucleotide sequencing of approximately 400 basepairs upstream from exon 1 of the DPB1 gene and sequence specific oligonucleotide hybridisation identified eight nucleotide positions to be polymorphic which were in linkage disequilibrium (LD) with DPA1 and DPB1 alleles. Substitutions at two sites (-230 and -224) formed three genotypes (DP-PRO1-3). DP-PRO 1 was the most common genotype and was in LD with DPA1*0103, *0202 and DPB1*0401, *0501. DP-PRO 2 was observed in LD with DPB1*02012, *1601, *1701 and DPA1*0104. DP-PRO3 was in LD with DPB1*0901, *1001 and DPA1*0201. Electrophoretic Mobility Shift Assays (EMSA) performed with restriction enzyme fragments showed substitutions at -230 and -224 not to be involved in binding nuclear proteins. Six substitutions were found on a single genotype (DP-PRO4) which was observed in seven samples; 67% of DP-PRO4 inferred haplotypes were HLA-A2-B46, DRB1*0901, DQB1*03032, DPA1*0401, DPB1*1301. Three of the substitutions occurred in conserved regulatory region boxes, W', X and Y, and three in the signal and leader sequences. EMSA competitive binding assays performed with oligonucleotide probes for the substitutions showed no difference in binding affinity for W' and X probes. The DP-PRO4 Y box had a decreased nuclear protein binding affinity compared to DP-PRO1-3. Whether the sum of the differences in DP-PRO4 relate to a change in the cell surface expression of HLA-DP is yet to be determined.

Binding Sites↗

PubMed1999

Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor.

With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of > 1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation.

Cell Line↗

PubMed1999

HLA-DPB1 alleles in house dust mite allergic patients.

Associations were sought between the presence of allergic sensitivity to Der p 1, a major allergen from the house dust mite, and the HLA-DPB1 genotype. Whilst allergic patients did not differ from controls in DPB1 allelic distribution, there was a correlation of DPB1*11011 with strongly reactive T-cell proliferative responses to Der p 1 and high titre specific IgE to Dermatophagoides pteronyssinus.

Alleles↗

PubMed1998

The Melbourne Pre-Diabetes Study: prediction of type 1 diabetes mellitus using antibody and metabolic testing.

OBJECTIVES: To determine the utility of various autoantibodies in predicting progression to clinical diabetes in first-degree relatives of patients with type 1 diabetes mellitus. PARTICIPANTS: 3315 first-degree relatives of patients with type 1 diabetes (1161 parents, 1206 siblings and 948 offspring) recruited through diabetes clinics, private endocrinologists, Diabetes Australia and the Juvenile Diabetes Foundation. MAIN OUTCOME MEASURES: Prevalence of islet cell antibodies (ICA) levels > or = 20 JDFu, insulin autoantibodies (IAA) levels > 100 nU/mL, and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine phosphatase IA2 (IA2Ab); change in beta cell function over time; and development of clinical diabetes. RESULTS: 2.6% of relatives had elevated ICA levels, 1.3% had elevated IAA levels and 0.3% had both. High ICA levels were significantly more frequent in siblings than in offspring or parents, and were more frequent in relatives younger than 20 years. GADAb were detected in 68% and IA2Ab in 57% of relatives with elevated ICA and/or IAA levels. Diabetes developed in 33 relatives (25 siblings, 2 offspring and 6 parents). Before diagnosis of clinical diabetes, high ICA levels were detected in 18 (58%), high IAA levels in 7 (23%), both in 5 (15%), and either in 19 (61%); GADAb were detected in 26 (84%), IA2Ab in 13 (42%), both in 11 (35%), and either in 28 (90%). First phase insulin release (FPIR) less than 50 mU/L was very strongly associated with progression to diabetes. In relatives with FPIR initially greater than 50 mU/L who eventually developed diabetes, there was a gradual and continuous reduction in FPIR over time before diagnosis. CONCLUSIONS: Type 1 diabetes can be diagnosed in the preclinical stage. The recently described antibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 appear superior to ICA as screening tools for the preclinical diagnosis of type 1 diabetes.

Adult↗