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Haplotyping or determination of genetic phase has always played a pivotal role in MHC (HLA studies) both in helping to understand inheritance patterns in diseases such as type 1 diabetes (T1D) and in ensuring better matching in... more
Haplotyping or determination of genetic phase has always played a pivotal role in MHC (HLA studies) both in helping to understand inheritance patterns in diseases such as type 1 diabetes (T1D) and in ensuring better matching in transplantation scenarios such as haematopoietic stem cell transplantation (HSCT), using donors genetically related to the patient. In recent years the need to establish genetic phase in a number of clinical scenarios has become apparent. These include: Genetic phasing for hematopoietic stem cell transplants using unrelated donors, where the HLA haplotypes are not known but where haplotype‐matched recipients fare better clinically than allele matched, but haplotype mismatched patients. The use of checkpoint inhibitors is one of the most innovative and exciting developments in cancer treatment in years. An example is the use of the monoclonal ipilimumab to block the CTLA‐4 receptor which is known to contain polymorphic sites. Until the phase of these polymorph...
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Research Interests: Immunology, Gastroenterology, Biology, Liver diseases, Humans, and 12 moreAutoimmune Disease, Chronic Disease, Hepatitis, Genetic linkage analysis, Clinical Sciences, Adult, Major histocompatibility complex, Neurosciences, Haplotype, Autoimmune Hepatitis, Human leukocyte antigen, and Paediatrics and reproductive medicine
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The heterogeneity within multisystem autoimmune disease was evaluated according to the presence of antinuclear antibodies to ribonucleoproteins and the HLA-A1, B8, DR3 phenotype. Patients with various multisystem autoimmune diseases were... more
The heterogeneity within multisystem autoimmune disease was evaluated according to the presence of antinuclear antibodies to ribonucleoproteins and the HLA-A1, B8, DR3 phenotype. Patients with various multisystem autoimmune diseases were tested by a highly sensitive radioimmunoassay for autoantibodies to the small nuclear ribonucleoproteins known as SS-B (La) and ribonucleoprotein (RNP), and HLA phenotypes were determined. The 210 patients included 64 with systemic lupus erythematosus (SLE), 11 with "atypical SLE", 41 with Sjögren's syndrome, 22 with mixed connective tissue disease (MCTD), 21 with rheumatoid arthritis (RA), 16 with primary biliary cirrhosis (PBC) and 35 with autoimmune chronic active hepatitis (A-CAH). Anti-SS-B (La) was present in high frequency in Sjögren's syndrome and was strongly associated with HLA-A1, B8, DR3. Anti-RNP was detected predominantly in MCTD and had no association with HLA-A1, B8, DR3. There were sharply defined serological and genetic differences between primary Sjögren's syndrome and Sjögren's syndrome associated with RA. Anti-SS-B (La) was present in 70% of patients with primary Sjögren's syndrome but in none with Sjögren's syndrome with RA, and the respective frequencies of HLA-A1, B8, and DR3 were 88%, 94% and 75% in the former compared with 38%, 29% and 14% in the latter. Thus primary Sjögren's syndrome differs immunogenetically from Sjögren's syndrome with RA. There was a notable absence of anti-SS-B (La) in PBC, an autoimmune disease associated with the Sjögren's syndrome. These findings illustrate the value of studying immunological and genetic markers in detecting heterogeneity within groups of diseases whose symptoms cannot be distinguished clinically.
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'Secondary failure' of oral hypoglycemics, in non-insulin dependent diabetics, has been attributed to dietary non-compliance, inadequate drug dosage, metabolic stress, or true drug failure. Progressive loss... more
'Secondary failure' of oral hypoglycemics, in non-insulin dependent diabetics, has been attributed to dietary non-compliance, inadequate drug dosage, metabolic stress, or true drug failure. Progressive loss of beta cell function is a suggested mechanism for true drug failure but on the basis of little documented evidence. In view of this, we have measured basal and glucagon-stimulated C-peptide levels, human leukocyte antigen (HLA) types, and islet cell antibodies in 20 non-insulin dependent diabetics with 'secondary failure' of oral agents. There were 16 females and four males with a mean ideal body weight of 1.30 units and mean duration of diabetes of 9.5 years. Fasting insulin (mean +/- SD: 15.1 +/- 10.6 mU/l) and fasting C-peptide (2.3 +/- 1.2 micrograms/l) were normal or slightly elevated in all but one patient. Mean C-peptide increased from 2.3 +/- 1.2 micrograms/l to 3.5 +/- 2.2 micrograms/l (152% over basal) 6 minutes after 1 mg i.v. glucagon. In 15 patients the C-peptide response was greater than 130% of basal. Islet cell cytoplasmic antibodies were detected in only two patients. The distribution of HLA types was not significantly different from a control population, with no increase in DR3 or DR4. Thus, absolute insulin deficiency is uncommon in non-insulin dependent diabetics with 'secondary failure' of oral hypoglycemic agents and such patients do not exhibit the immuno-genetic markers of insulin-dependent diabetes.
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The leukocyte migration test was used to detect cellular immunity to HL-A antigens present on the husband's lymphocytes and spermatozoa in a group of fertile and infertile couples. Approximately 50% of the married female... more
The leukocyte migration test was used to detect cellular immunity to HL-A antigens present on the husband's lymphocytes and spermatozoa in a group of fertile and infertile couples. Approximately 50% of the married female population appear to be sensitized. There was no difference between the fertile and infertile groups in the frequency of positive results, but a greater number of migration indices were below 0.7 and 0.6 in the infertile group. It is suggested that sperm cells are the most likely cause of immunization.
Research Interests: Andrology, Immunology, Biology, Infertility, Medicine, and 15 morePopulation, Humans, Immunity, Fertility and Sterility, Female, Sperm, Male, Immunization, Clinical Sciences, Cellular Immunity, Public health systems and services research, Antigen, Clinical Trials as Topic, Lymphocyte, and Paediatrics and reproductive medicine
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Eighty-five couples with habitual abortion were studied: 43 were primary aborters (i.e., had no advanced pregnancy beyond 20 weeks gestation), and 42 were secondary aborters. The only significant finding in primary female aborters was a... more
Eighty-five couples with habitual abortion were studied: 43 were primary aborters (i.e., had no advanced pregnancy beyond 20 weeks gestation), and 42 were secondary aborters. The only significant finding in primary female aborters was a reduction in the incidence of B35. In contrast, in secondary female aborters there was a reduction in the incidence of DR3 and A1/B8/DR3 and an increase in the degree of homozygosity of HLA B. In the male partners of primary aborters, there was a reduced incidence of DR3 and A1/B8/DR3. In addition, in male partners of both primary and secondary aborters, there was increased HLA-B homozygosity and increased frequency of DR4-5 phenotype. Increased sharing of HLA antigens between partners was not found to be significantly different from the control population. These findings emphasize that primary and secondary female aborters form distinct populations, which could explain differences in immunological responses to various antigens, including fetal-related antigens. The closely related findings in female secondary aborters and male partners of primary aborters are intriguing but cannot be explained. Whether or not these genetic markers bear any relationship to reproductive success remains to be determined.
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Nineteen insulin dependent diabetics with onset at 30 years of age or less and duration of diabetes of greater than 25 years were divided into two groups on the basis of the presence or absence of clinically evident vascular disease. The... more
Nineteen insulin dependent diabetics with onset at 30 years of age or less and duration of diabetes of greater than 25 years were divided into two groups on the basis of the presence or absence of clinically evident vascular disease. The patients without vascular disease were characterised by a later mean age of onset, lower fasting growth hormone concentration, and a lower frequency of the unusual HLA pattern B8 without A1 compared to the diabetics with vascular complications. The level of blood glucose control assessed over the last 15 years, insulin antibody titres, plasma glucagon levels and plasma cholesterol did not differ between the two groups. Residual beta cell activity was found in only one of the 19 patients. Although this study does not exclude an effect of the degree of blood glucose control or persistence of beta cell function in the early stages of diabetes on the subsequent development of vascular disease, it suggests that genetic factors, age of onset and plasma growth hormone levels may be more important.
Research Interests: Endocrinology, Medicine, Growth Hormone, Humans, Internal Medicine, and 15 moreBlood Glucose, Insulin, Glucagon, Diabetes mellitus, Female, Male, Clinical Sciences, Middle Aged, Adult, Public health systems and services research, Hormone, Blood Sugar, Age Factors, islets of Langerhans, and Vascular Disease
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Research Interests: Exploration and Antibody
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ABSTRACT
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A possible immunogenetic basis for diabetes in chronic pancreatitis was explored by studying 19 patients with both disorders, most of whom required treatment with insulin. In contrast to patients with insulin-dependent (Type 1) diabetes,... more
A possible immunogenetic basis for diabetes in chronic pancreatitis was explored by studying 19 patients with both disorders, most of whom required treatment with insulin. In contrast to patients with insulin-dependent (Type 1) diabetes, patients with diabetes and chronic pancreatitis had residual beta cell function but blunted C-peptide responses to intravenous glucagon, absence of circulating islet cell antibodies, and HLA-DR types similar to control subjects and patients with chronic pancreatitis without diabetes. Diabetes complicating chronic pancreatitis is therefore not associated with the biochemical or immunogenetic markers characteristic of Type 1 diabetes.
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An immunogenetic study of autoimmune chronic active hepatitis (CAH) showed the relative risk (RR) for this disease was 11.6 for patients who were HLA-B8, 11.7 for patients who were DR3 and 2.3 for patients who were Gma+x+. Moreover, the... more
An immunogenetic study of autoimmune chronic active hepatitis (CAH) showed the relative risk (RR) for this disease was 11.6 for patients who were HLA-B8, 11.7 for patients who were DR3 and 2.3 for patients who were Gma+x+. Moreover, the Gm haplotype Gma+x+ was present in 18 of 40 (45%) patients with HLA-B8, but in none of 10 patients negative for HLA-B8, whereas in 180 healthy controls Gma+x+ was evenly distributed among those positive (24%) and negative (18%) for HLA-B8. The RR was lowest in patients lacking HLA-B8 but positive for Gma+x+. Relative to this low-risk group, the risk was increased 39 times in subjects with both HLA-B8 and Gma+x+, 15 times in subjects with HLA-B8 who were not Gma+x+ and twice in subjects who were neither HLA-B8 nor Gma+x+. Statistical analysis indicated that the three-factor effect (disease risk affected by non-additive effects of HLA-B8 and Gma+x+) was significant (P less than 0.01), as were the main effects of HLA-B8 (P less than 0.001) and Gma+x+ (P...
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www.microbiol.unimelb.edu.au/14ihiws / 14 th International HLA and Immunogenetics Workshop and Conference
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... 2, June 1991 Copyright 1991, by Bailli~re Tindall ISBN 0-7020-1490-7 All rights of reproduction in any form reserved 212 BD TAIT AND LC HARRISON be the Bw62 subtype) were increased in frequency in Caucasoid IDDM patients (Singal and... more
... 2, June 1991 Copyright 1991, by Bailli~re Tindall ISBN 0-7020-1490-7 All rights of reproduction in any form reserved 212 BD TAIT AND LC HARRISON be the Bw62 subtype) were increased in frequency in Caucasoid IDDM patients (Singal and Blajchman, 1973; Cudworth and ...
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A survey of patients with skin cancer in southern Australia detected that the development of multiple BCCs is common. The incidence of multiple BCCs peaks during the sixth decade and reaches a plateau. Human leukocyte antigen (HLA) DR1... more
A survey of patients with skin cancer in southern Australia detected that the development of multiple BCCs is common. The incidence of multiple BCCs peaks during the sixth decade and reaches a plateau. Human leukocyte antigen (HLA) DR1 was associated with the development of multiple BCCs in people under the age of 55, but not in older people.
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Page 1. 0041-1337/79/2705-0324$02.00/0 Transplantation Copyright © 1979 by The WUliams & Wilkins Co. Vol. 27, No. 5 Printed in USA IMPROVED SURVIVAL AND FUNCTION OF RENAL TRANSPLANTS WITH POSITIVE ...
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Cellular reactivity to Der p 2, a major allergen of the house dust mite (HDM) Dermatophagoides pteronyssinus, was studied in a group of 41 symptomatic HDM sensitive patients, using fresh peripheral blood mononuclear cells (PBMC) and... more
Cellular reactivity to Der p 2, a major allergen of the house dust mite (HDM) Dermatophagoides pteronyssinus, was studied in a group of 41 symptomatic HDM sensitive patients, using fresh peripheral blood mononuclear cells (PBMC) and assays of proliferation. Sixty per cent of the patients responded to Der p2, with reactivities being greater in patients with asthma as one of their clinical manifestations and also in those who had skin-test reactivity to a number of allergens. HLA-DR and -DQ serotyping was undertaken in 39 of the patients and the magnitude of T-cell proliferative responses to Der p 2 were found to be positively associated with DQ7 and negatively associated with DQ2. T-cell determinants within the Der p 2 molecule were identified by assays using a series of overlapping peptides (15- to 19-mers) spanning the entire protein. Fifty-nine per cent of the 41 HDM-sensitive patients responded to one or more of the peptides. All of the peptides were antigenic for at least one of...
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Two hundred healthy adults were immunized with 1 microgram of the bacterial antigen monomeric flagellin from Salmonella adelaide, and grouped as responders and non-responders on the basis of a rise in titre of antibody 2 weeks after... more
Two hundred healthy adults were immunized with 1 microgram of the bacterial antigen monomeric flagellin from Salmonella adelaide, and grouped as responders and non-responders on the basis of a rise in titre of antibody 2 weeks after immunization. Immunoglobulin allotypes G1m(a), G1m(z) and G3m(g) were more frequent among responders who made immunoglobulin (Ig)G antibody (P less than 0.02), and HLA-B12 was more frequent among responders who made IgM antibody (P less than 0.05). The mean log titre of IgG antibody was higher in females (P less than 0.001), in subjects with T1m(a), G1m(z) and G3m(g) allotypes (P less than 0.05), and in Gm heterozygotes (P less than 0.01). The mean log titre of the IgG antibody response in subjects with particular Gm phenotypes was also dependent on the HLA-B locus phenotypes HLA-B7, B8 and B12 (P less than 0.005); for example, among those with the phenotype Gm(a-x-b) subjects with HLA-B7 were low responders and those with HLA-B8 were high responders. Th...
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Studies of T lymphocyte subsets were carried out in a group of 50 scleroderma patients, of whom 46 were also HLA phenotyped. The total lymphocyte count was depressed in 22 patients, and CD4 (helper cells) numbers were normal. CD8... more
Studies of T lymphocyte subsets were carried out in a group of 50 scleroderma patients, of whom 46 were also HLA phenotyped. The total lymphocyte count was depressed in 22 patients, and CD4 (helper cells) numbers were normal. CD8 (suppressor-cytotoxic) cells were reduced in 27 patients, and the CD4/CD8 number ratio increased above normal in three additional patients, resulting in 30 patients being classified as CD8-deficient. In the 46 patients HLA phenotyped, DRw8 was significantly increased in the entire patient group, but when the patients were subdivided into CD8-deficient (n = 29) and CD8-normal (n = 17), the increase in DRw8 was confined to the CD8-deficient patients. B18 was also increased in patients with limited sclerosis, while DR4 and DRw53 were significantly decreased and DR5 significantly increased in patients with more extensive skin sclerosis. These findings suggest that scleroderma is a heterogeneous condition and that this heterogeneity is reflected in different HLA...
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One hundred and twelve hospital based outpatients with rheumatoid arthritis (mean duration +/- standard error, 10.7 +/- 0.9 years) were studied for radiological progression of the hands and wrists over a mean period of 26.5 +/- 0.5... more
One hundred and twelve hospital based outpatients with rheumatoid arthritis (mean duration +/- standard error, 10.7 +/- 0.9 years) were studied for radiological progression of the hands and wrists over a mean period of 26.5 +/- 0.5 months. The majority were taking slow acting antirheumatic drugs (SAARD). The rate of radiographic progression was positively and independently associated with the female sex (p less than 0.01), erythrocyte sedimentation rate (ESR, p less than 0.05) and HLA-DR1 (p less than 0.05). There was a negative association with HLA-DR4 (p less than 0.05) but this was no longer significant after adjusting for ESR. There was no relationship between the rate of radiological progression and the presence of rheumatoid factor, rheumatoid nodules and duration of treatment with SAARD.
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An assay of cell-mediated immunity, the leucocyte migration technique (LMT), has been compared with the commonly used assay of humoral immunity to transplantation antigens, the microlymphocytotoxicity test. Five recently multiply... more
An assay of cell-mediated immunity, the leucocyte migration technique (LMT), has been compared with the commonly used assay of humoral immunity to transplantation antigens, the microlymphocytotoxicity test. Five recently multiply transfused patients and nineteen haemodialysis patients who had been potentially immunized against transplantation antigens were studied by both tests. All five transfused patients gave positive LMT results while only two gave a positive serological test. Sixteen out of nineteen dialysis patients gave positive LMT results compared with nine with known anti-HL-A antibodies and four showing positive serological direct cross-matches. There was no correlation between cell-mediated and humoral immunity as detected by these methods, although there was a tendency, which was not absolute, for positive direct cross-matches between patients' sera and the panel's lymphocytes, to be associated with positive LMT results. There was a significant correlation (P le...
Research Interests: Immunology, Medicine, Serology, Transplantation, Humans, and 8 moreImmunity, Male, Antibody, Adult, Blood Transfusion, Leukocytes, Antigen, and Renal Dialysis
HLA phenotypes of 66 parents of 33 infants succumbing to the sudden infant death syndrome (SIDS) were determined using a standard microlymphocytotoxicity method. Heterogeneity testing over all locus antigens revealed a significant... more
HLA phenotypes of 66 parents of 33 infants succumbing to the sudden infant death syndrome (SIDS) were determined using a standard microlymphocytotoxicity method. Heterogeneity testing over all locus antigens revealed a significant difference between the parents and a control group consisting of blood donors and healthy unrelated volunteers. This heterogeneity was still evident when maternal and paternal groups were considered separately with the controls and when compared with each other. Individual A locus antigens displaying frequency deviation from control values included A9 (decreased in husbands), A10 (increased in wives and total parent group), and A28 (increased in wives). The increase in frequency of A10 became highly significant when only parents of children with evidence of laryngitis at post mortem were used for comparison with control values. No difference in B locus antigens between any of the groups was observed. The results obtained are compatible with the view that S...
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ABSTRACT
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As the cause of allograft heart valve degeneration is poorly understood, the study aim was to investigate the host antibody response to allograft valve implantation. Sera were obtained from 92 recipients of allograft heart valves (61... more
As the cause of allograft heart valve degeneration is poorly understood, the study aim was to investigate the host antibody response to allograft valve implantation. Sera were obtained from 92 recipients of allograft heart valves (61 pulmonary, 31 aortic). Sera were tested for anti-HLA class I antibodies by ELISA and complement-dependent cytotoxicity (CDC) methods, and anti-HLA class II antibodies by ELISA. Specificities of recipient anti-HLA class I antibodies were defined by standard CDC testing against a panel of T lymphocytes from 80 blood donors. Donor valve HLA typing was performed on stored donor DNA samples using molecular methods. The presence of donor-specific anti-HLA class I antibodies was hence defined in recipient sera. The presence of anti-HLA antibodies and donor-specific anti-HLA class I antibodies were correlated with function of allograft valves at the most recent echocardiographic follow up. At a mean of 3.0 years (range: 0.3-5.4 years) after allograft implantati...
Research Interests: Immunology, Cryopreservation, Adolescent, Medicine, Antibodies, and 15 moreHumans, Female, Male, Organ Preservation, Cadaver, Aged, Middle Aged, Heart valves, Antibody, Adult, Cross Sectional Studies, Heart Valve Prosthesis Implantation, Human leukocyte antigen, Heart valve disease, and Cardiovascular medicine and haematology
HLA D locus-related (DR) antigens and Gm phenotypes were determined in 30 patients with epidemic polyarthritis following Ross River virus (RRV) infection and contrasted with those in comparison series of 119 (DR) and 1220 (Gm) normal... more
HLA D locus-related (DR) antigens and Gm phenotypes were determined in 30 patients with epidemic polyarthritis following Ross River virus (RRV) infection and contrasted with those in comparison series of 119 (DR) and 1220 (Gm) normal subjects. HLA DR7 (46.7% cf. 21.0%) and the heterozygous Gm phenotype a+x+b+ (33.3% cf. 15.3%) were significantly increased in the patients, with relative risks of 3.3 and 2.8 respectively. The occurrence of Gm a+x+b+ was independent of DR7, and conferred a relative risk of 4.3 in DR7-negative patients. Differences found in clinical features, specific lymphocyte proliferative responses and antibody titres did not reach significant levels. The association with DR7 was inversely related to age in residents of an area of moderate endemic risk, and to levels of natural cell-mediated immunity (natural killer cell activity). These correlations point to possible mechanisms by which genetic traits might influence the occurrence or consequence of RRV infection.
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In a 3-centre study involving 144 patients with rheumatoid arthritis (RA), a relationship between side effects from D-penicillamine and HLA antigens, allotypic markers of the IgG heavy chain (Gm) and allotypes of complement components Bf,... more
In a 3-centre study involving 144 patients with rheumatoid arthritis (RA), a relationship between side effects from D-penicillamine and HLA antigens, allotypic markers of the IgG heavy chain (Gm) and allotypes of complement components Bf, C4A and C4B was sought. There was a significant association between proteinuria induced by D-penicillamine and the antigens DR3 and B8. However, the presence of DR2 seemed to protect against the development of proteinuria. Thrombocytopenia from D-penicillamine was significantly associated with HLA-A1 and DR4; 15 of 23 patients who possessed both antigens developed thrombocytopenia (p less than 0.001 uncorrected, approximate relative risk (RR) = 5.5). A null complement allele located at the C4B locus (C4BQO) was also associated with thrombocytopenia from D-penicillamine (p less than 0.005, RR = 17.3). Our study confirms the findings from other series which indicate that there is a genetic predisposition for the development of proteinuria from D-peni...