Biomedical subjects

C S Witt

Publications and source records attributed to C S Witt.

At least 19 recordsLinked to original sources

PubMed2006

MICA, MICB, and MHC beta block matching in bone marrow transplantation: relevance to transplantation outcome.

Genetic testing of the MHC is required for selection of donors for bone marrow transplantation. The outcome of related bone marrow transplantation is usually superior to that of unrelated bone marrow transplantation. This may be the result of inaccurate or incomplete genetic testing employed for selection of donor for transplantation. Based on MHC haplotype matching, MHC block matching has been developed for selection of potential unrelated donor. Block matching has been shown previously to improve outcome when added to the conventional method of human leukocyte antigen (HLA) typing for selection of donors. In this study, we have retrospectively analyzed 44 donor recipient pairs from the Australian Bone Marrow Donor Registry Repository with respect to matching of HLA-B and HLA-Cw by sequence-based typing and MICA and MICB by polymerase chain reaction-sequence specific primer and MHC beta block matching and correlated these results with survival. Beta block matching was correlated with MIC matching (p < 0.005) and with HLA-B and HLA-Cw matching. Patients who were HLA-B and -Cw matched had significantly improved survival when they were additionally matched for MHC beta block (p(c) = 0.04) or MIC (p(c) = 0.05).

Adolescent↗

PubMed2006

The relevance of natural killer cell human leucocyte antigen epitopes and killer cell immunoglobulin-like receptors in bone marrow transplantation.

The discovery that killer cell immunoglobulin-like receptors (KIR) interact with genetically polymorphic epitopes on class I human leucocyte antigen (HLA) molecules and that the KIR receptor repertoire itself is genetically variable has led to investigation of the relevance of the KIR system to stem cell transplantation. A number of retrospective studies of transplant outcome have now demonstrated either beneficial or deleterious effects of mismatching for class I natural killer (NK) epitopes. A smaller number of studies have shown effects of the donor and/or patient KIR repertoire on outcome, irrespective of the patient and donor HLA type. The most parsimonious interpretation of the data, which are often conflicting, is that the effect of NK epitope matching is very much dependent on transplant protocols, with the extent of donor T-cell depletion possibly being the most important variable. A clearer picture of the role of matching for NK epitopes and the KIR-receptor repertoire of the donor is needed.

Bone Marrow Transplantation↗

PubMed2005

Menopausal hormone therapy and irregular endometrial bleeding: a potential role for uterine natural killer cells?

CONTEXT: Irregular bleeding affects many users of combined menopausal hormone therapy (HT) and commonly leads to invasive and expensive investigations to exclude underlying malignancy. In most cases no abnormality is found. OBJECTIVE: The main objective of this study was to explore the role of uterine natural killer (uNK) cells and their regulatory cytokine IL-15 in irregular bleeding in HT users. DESIGN: This was a prospective observational study conducted between 2002 and 2004. SETTING: The study was conducted in a tertiary referral menopause clinic at King Edward Memorial Hospital, Western Australia. PATIENTS: Patients included 117 postmenopausal women taking combined HT. INTERVENTIONS: Outpatient endometrial biopsies were taken during and outside bleeding episodes. MAIN OUTCOME MEASURES: The relationship between endometrial uNK cells (CD56+) and bleeding patterns was measured. We also addressed the impact of HT exposure on uNK cell populations, the relationship between endometrial IL-15 expression and uNK cell populations, and killer Ig like receptor genotype in subjects with irregular bleeding. RESULTS: Endometrial CD56+ uNK cells were significantly increased in biopsies obtained during bleeding episodes (P < 0.001), compared with HT users with no bleeding. The highest level of IL-15 expression was also seen in biopsies taken during bleeding. No clear relationship between killer Ig like receptor genotype and bleeding on HT was observed. CONCLUSIONS: Little is known about the mechanisms underlying irregular bleeding in HT users. This is the first report of uNK cells and their association with regulating cytokines in postmenopausal endometrium and demonstrates a possible mechanism by which HT may induce irregular bleeding.

CD56 Antigen↗

PubMed2005

Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression.

Variation in the host response to infection by pathogens including HIV-1 may be conferred by polymorphic genetic factors such as HLA and killer immunoglobulin-like receptors (KIR) genes. Here, we examined KIR and HLA genotype effects on pretreatment viral load, rate of CD4(+) T-cell decline and progression to AIDS among adult HIV-1-infected patients within the Western Australian HIV Study Cohort. In this study, carriage of KIR genes within the 'B' haplotype (eg KIR2DS2) was specifically associated with a more rapid CD4(+) T-cell decline over time and progression to AIDS. In contrast, KIR gene repertoire had no effect on pretreatment viral load while selected HLA alleles (eg HLA-B*5701, HLA-B*2705) demonstrated significant protective effects on viremia. Furthermore, interactions between specific HLA and KIR genes did appear to influence HIV disease progression. The results suggest that host genetic variation within the HLA and KIR gene complexes have clinically relevant effects on the course of HIV-1/AIDS, acting independently as well as synergistically to modify disease progression at multiple levels.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Natural killer cell HLA-C epitopes and killer cell immunoglobulin-like receptors both influence outcome of mismatched unrelated donor bone marrow transplants.

Matching of donor and recipient for the class I human leukocyte antigen-C (HLA-C)-encoded natural killer (NK) epitopes has been reported to influence stem-cell (SC) graft outcome, but a consistent picture has not yet emerged. We have analyzed transplant outcome in 104 unrelated SC grafts in relation to NK epitope (C1 and C2) matching and donor killer cell immunoglobulin-like receptor (KIR) genotype. NK epitope mismatching in the rejection direction was strongly associated with an increased probability of rejection subsequent to engraftment. The prevalence of grades III-IV acute graft-vs-host disease (GVHD) was significantly higher and occurred significantly earlier when there was NK epitope mismatching in the GVH direction. Higher transplant-related mortality and lower disease-free survival rates were associated with epitope mismatching regardless of the mismatch direction. A greater number of KIR receptors, both activating and inhibitory, in the donor protected against grades III-IV GVHD and improved survival.

Adolescent↗

PubMed2004

Maternal KIR repertoire is not associated with recurrent spontaneous abortion.

BACKGROUND: In view of evidence suggesting an immunological cause of recurrent spontaneous abortions (RSA) and the large number of maternal natural killer (NK) cells present in the pregnant uterus, we investigated the genetic polymorphism of the killer cell immunoglobulin-like receptors (KIR) in women with RSA. METHODS: KIR gene repertoire and KIR2DL4 (a receptor for HLA-G) genotyping were determined by SSP and SSCP respectively, in women experiencing RSA and controls. RESULTS: The KIR repertoire did not differ between RSA patients and controls in terms of: (i) the number of inhibitory receptors; (ii) the number of activating receptors; (iii) the ratio of inhibitory to activating receptors. KIR2DL4, a receptor for HLA-G, has different transmembrane alleles, which produce functionally different phenotypes. The frequency of KIR2DL4 transmembrane genotypes differed significantly between RSA patients and controls (P=0.03). However, although homozygosity for a membrane-bound receptor was more frequent in patients (25%) than controls (10%), other genotypes that would produce the same phenotype were not more frequent in patients than controls. CONCLUSIONS: The data provide little evidence that KIR polymorphism plays a role in predisposition to RSA.

Abortion, Habitual↗

PubMed2002

The effects of a low frequency acoustic waveform on peripheral vascular disease: a pilot study.

OBJECTIVE: To evaluate the effects of a low frequency acoustic waveform on peripheral vascular disease (PVD). DESIGN: Pilot study utilizing a one-group pre-intervention, post-intervention design. SETTING: Adults with peripheral vascular disease were recruited through local advertisements. The study was conducted at a local facility housing the electroacoustic transducer. INTERVENTION: A 25-min exposure to an electroacoustic transducer. OUTCOME MEASURES: Pre- and post-measurement of Doppler ultrasound blood-flow velocities in 10 arteries, ankle brachial index (RBI), foot assessment, and 1-week post telephone survey. RESULTS: A significant increase was noted in the right ankle brachial index (RABI) but not the left. Blood flow increased in all arteries, significantly in four. Thirteen participants reported improvement in symptom of peripheral vascular disease over the following week. CONCLUSIONS: While conclusions must be viewed cautiously, the significant differences noted warrant further study to examine effects of acoustic waveforms on peripheral vascular disease.

Acoustics↗

PubMed2002

Common HLA-B8-DR3 haplotype in Northern India is different from that found in Europe.

The aim of this study was to determine whether a common diabetic haplotype, including human leukocyte antigen (HLA)-B8 and HLA-DR3, in Northern India is the same haplotype as the European HLA-B8-DR3 haplotype. DNA samples from Northern Indian subjects selected on the basis of HLA-B8 and HLA-DR3 were tested for microsatellite and single nucleotide polymorphism alleles throughout the major histocompatibility complex (MHC). It was found that the Indian samples represent a conserved haplotype in which all alleles were shared by Indian subjects with HLA-B8 and HLA-DR3, but were different to those that are characteristic of the European 8.1 ancestral haplotype. The Indian and European haplotypes share HLA-B*0801, HLA-DRB1*0301 and HLA-DQB1*02 but differ for subtypes of HLA-Cw*07 and HLA-DRB3 and all central MHC alleles tested. In contrast, Indian subjects selected on the basis of HLA-B58 ( 1-17) and HLA-DR3 shared the same alleles at other MHC loci as have been described in the common Chinese haplotype with HLA-B58/17 and HLA-DR3. A third haplotype, HLA-B50/21 and HLA-DR3, was also found to be highly conserved but shares little in common with the other two HLA-DR3-containing Indian haplotypes.

Diabetes Mellitus, Type 1↗

PubMed2001

Localization of central MHC genes influencing type I diabetes.

The contribution of MHC class II haplotypes to susceptibility to type I diabetes has been clearly established, and interest has now focused on the effects of additional genes in the MHC region. We have investigated the central MHC alleles on 8.1 ancestral haplotype (HLA-A1, B8, DR3, DQ2), as it is well conserved in Caucasian populations. The HLA-DR3-DQ2 genotype is a recognized risk factor for type I diabetes. Single nucleotide polymorphisms and microsatellites in the MHC were used to map segments of the 8.1 ancestral haplotype carried by type I diabetic and control subjects expressing either HLA-B8 or DR3, but not both these markers. In this way we controlled for the diabetogenic effect of carriage of DR3. Alleles of the 8.1 ancestral haplotype between TNFA-308/D6STNFa and HLA-B were carried with significantly greater frequency in B8(-), DR3(+) type I diabetic patients compared with B8(-), DR3(+) controls. This interval was marked by a BAT1 gene polymorphism and a MIB microsatellite allele.

Alleles↗

PubMed2001

Can MHC class II genes mediate resistance to type 1 diabetes?

Numerous studies have associated carriage of HLA-DRB1*1501, DQA1*0102 and DQB1*0602 (DR15, DQ6) with dominant resistance to type 1 diabetes and have concluded that one or more of the component HLA class II molecules mediate this effect. Mechanisms for MHC class II-mediated resistance to diabetes have been proposed from studies of transgenic mice, usually using the diabetes-prone non-obese diabetic (NOD) strain. However, these studies have not reached any consensus on a plausible mechanism. In this study we question why the role of central MHC genes in resistance to diabetes has not been addressed, as the central MHC carries markers of susceptibility to diabetes in linkage disequilibrium with several genes with known or putative immunoregulatory functions. To illustrate the type of studies required to address this issue, we selected diabetes patients and control subjects for carriage of HLA-DR15 and the C allele at position +738 in the inhibitor of kappa B-like gene (IKBL). These alleles mark the 7.1 haplotype (HLA-A3, B7, IKBL738*C, DR15, DQ6). HLA-DR15 was the most effective marker of resistance, but an effect may be evident with IKBL738*C in a larger study. Moreover, carriage of the entire haplotype was particularly rare in patients. The best explanation for this is that the critical gene lies between IKBL and HLA-DRB1, and is more closely linked to HLA-DRB1. Candidate genes at the centromeric end of the central MHC are reviewed, highlighting the need for further study.

Adult↗

PubMed2000

The genomic organization and evolution of the natural killer immunoglobulin-like receptor (KIR) gene cluster.

Natural killer (NK) immunoglobulin-like receptors (KIRs) are a family of polymorphic receptors which interact with specific motifs on HLA class I molecules and modulate NK cytolytic activity. In this study, we analyzed a recently sequenced subgenomic region on chromosome 19q13.4 containing eight members of the KIR receptor repertoire. Six members are clustered within a 100-kb continuous sequence. These genes include a previously unpublished member of the KIR gene family 2DS6, as well as 2DL1, 2DL4, 3DL1, 2DS4, 3DL2, from centromere to telomere. Two additional KIR genes, KIRCI and 2DL3, which may be located centromeric of this cluster were also analyzed. We show that the KIR genes have undergone repeated gene duplications. Diversification between the genes has occurred postduplication primarily as a result of retroelement indels and gene truncation. Using pre- and postduplication Alu sequences identified within these genes as evolutionary molecular clocks, the evolution and duplication of this gene cluster is estimated to have occurred 30-45 million years ago, during primate evolution. A proposed model of the duplication history of the KIR gene family leading to their present organization is presented.

Alleles↗

PubMed2000

Detection of KIR2DL4 alleles by sequencing and SSCP reveals a common allele with a shortened cytoplasmic tail.

Single-stranded conformation polymorphism (SSCP) by capillary electrophoresis was assessed as a screening and typing method for alleles of KIR2DL4. Exon 6 was investigated as this exon was reported to include three polymorphic nucleotides. Exon 6, intron 6 and exon 7 were amplified as a single polymerase chain reaction (PCR) product of 650 bp from genomic DNA. The PCR product was sequenced and analysed by SSCP. Exon 7 was found to be invariant. Only two nucleotides were found to be polymorphic in exon 6 and another three were found in intron 6. Strong linkage disequilibrium was found between the polymorphic nucleotides resulting in the presence of three alleles in a panel of 20 cell lines. Two alleles differed within intron 6 while the third allele differed at two nucleotides in exon 6. All six possible genotypes were distinguishable by SSCP providing information from both the forward and reverse primers was used. Exon 6 of one allele was one nucleotide shorter than that of the other alleles and the resulting frame shift is predicted to produce a truncated cytoplasmic tail due to a premature stop codon four codons into exon 7. SSCP was found to be an efficient method of typing exons 6 and 7 in a panel of 46 bone marrow donors. All three alleles were found to be common and one was in strong linkage disequilibrium with the presence of another KIR sequence KIR3DS1.

Alleles↗

PubMed1999

Population frequencies and putative haplotypes of the killer cell immunoglobulin-like receptor sequences and evidence for recombination.

BACKGROUND: The killer cell immunoglobulin-like receptors (KIR) are a family of receptors expressed on natural killer (NK) cells and some T cells. Class I HLA molecules on target cells are the ligands for the KIR receptors. The number of KIR genes has been reported to vary between individuals, resulting in different KIR haplotypes. There is little published data on the frequency of each KIR gene and the linkage disequilibrium between the genes. Because there is evidence that NK cells may be involved in bone marrow transplant rejection, we have determined the KIR gene frequencies and possible haplotypic arrangements by linkage disequilibrium analysis in an Australian population. METHODS: Controls, patients with leukemia, and unrelated bone marrow donor-recipient pairs were typed for the presence of 11 KIR genes by polymerase chain reaction-sequence specific priming. RESULTS: Ninety percent of the population was found to have a sufficient number and variety of KIR genes to detect any mismatch of HLA-A, -B, and -C alleles on NK target cells. The 11 KIR genes could be divided into two groups based on linkage disequilibrium between pairs of genes. Evidence for a recombination within the KIR gene complex is presented. CONCLUSION: Typing for the presence of particular KIR genes may be indicated for bone marrow donor-recipient pairs for whom a class I HLA mismatch is unavoidable.

Bone Marrow Transplantation↗

PubMed1999

Mapping of a candidate region for susceptibility to inclusion body myositis in the human major histocompatibility complex.

Inclusion body myositis (IBM) is a form of idiopathic inflammatory myopathy of unknown aetiology. A strong association with HLA class II (HLA-DR3) suggested a role for genes in the human major histocompatibility complex (MHC) in the predisposition to this disease. In this study, we have taken advantage of the ancestral haplotype (AH) concept and historical recombinations to map for a possible susceptibility gene(s) in the MHC. We performed detailed typing of three MHC-related HSP70 genes and defined allelic combinations in the context of MHC AH. We also modified existing methods to give a simple and accurate method for typing two TNF microsatellites. Using the HSP70 and TNF markers and HLA-DR, -B, and C4 typing of our patients with IBM, we defined a potential site for the MHC-associated susceptibility gene(s) in the region between HLA-DR and C4.

Alleles↗

PubMed1999

Reconstruction of the block matching profiles.

Block matching is a valuable tool for selecting donors for bone marrow transplantation. Identical, electrophoretic profiles of unrelated bone marrow donor-recipient pairs have been shown to be associated with long-term survival and a reduction of graft versus host disease (GVHD). This study was undertaken to determine the sequences of the PCR products which are generated. PCR products obtained with beta-block primers following the amplification of DNA extracted from cell lines homozygous for 7.1 and 8.1 ancestral haplotypes were cloned and sequenced. The PCR products were characterised and the beta block profiles reconstructed. The data indicate that the profiles consist of homoduplexes and heteroduplexes which are formed by the products of probably 3 different sequence locations.

Cell Line, Transformed↗

PubMed1999

Molecular analysis of HLA class II polymorphisms among different ethnic groups in Israel.

The Jewish population in Israel comprises of inhabitants of heterogeneous ethnic backgrounds. Genetic studies classify the Israeli Jewish population into two major groups: Ashkenazi from Central and Eastern Europe and Sephardic or non Ashkenazi, from the Mediterranean and North Africa. The present study was aimed at elucidating the differential influx of HLA class II alleles in Ashkenazi, in various non-Ashkenazi subgroups and in Israeli Moslem Arabs. Using the PCR-SSOP technique, a large number of alleles were detected at each of the loci examined (DRB1, DQA1 and DQB1). In addition, gene frequencies, characteristic DR/DQ linkage disequilibria, population distance and their corresponding dendogram, were used to study the relationship between Israelis as a group, non Jewish Caucasians and Blacks. These populations could be grouped into three main clusters: the first consists of all the Israeli groups with the exception of the Ethiopian Jews; the second consists of non Jewish Caucasians, with a clear distinction seen between Israelis and non Jewish Europeans and U.S. Caucasians; the third, composed of Blacks, is distinctly different from the other populations. Ethiopian Jews were found to be closer to the Blacks than to any of the Israeli Jewish groups. We have shown that Jews share common features, a fact that points to a common ancestry. A certain degree of admixture with their pre-immigration neighbors exists despite the cultural and religious constraints against intermarriage.

Alleles↗

PubMed1999

The significance of HLA matching in cardiac transplantation.

It is argued that HLA matching is not worthwhile in heart transplantation. However, transplanting HLA compatible hearts enhances graft survival and should significantly reduce infection and malignancies related to aggressive immunosuppression. It is our view that the problem is technical and we offer a potential solution.

Graft Survival↗

PubMed1999

Periodontal attachment loss in HIV-infected patients is associated with the major histocompatibility complex 8.1 haplotype (HLA-A1,B8,DR3).

Periodontal attachment loss is mediated by overproduction of tumour necrosis factor (TNF) and interleukin (IL)-1, and appears to have a genetic component. The 8.1 major histocompatibility complex (MHC) ancestral haplotype (HLA-A1,B8,TNFA-308(2),DR3) is associated with elevated TNF production and predisposes carriers to several autoimmune/immunopathological disorders, including rapid progression of HIV disease, but not early onset periodontal disease in healthy individuals. Rather a high proportion of subjects with severe periodontal disease carry allele 2 at IL-1A-889 and IL-1B+3953. We predicted that genetic associations may be different or clearer in HIV patients, as they often show elevated production of TNF and IL-1 and periodontal attachment loss. Hence periodontal parameters and IL-1 polymorphisms were assessed in HIV-positive subjects expressing HLA-B8 with or without other markers of the 8.1 haplotype. Of 16 HLA-B8 subjects, 13 demonstrated elevated probing pocket depth and clinical attachment loss. The difference was statistically significant and did not correlate with smoking, age, CD4 T-cell counts, HIV viral load or levels of dental plaque. As TNFA-308 (allele 2) was present in four non-B8 subjects who had minimal attachment loss, it may not mediate the effect of the 8.1 haplotype. Moreover, polymorphisms at IL-1A-889 and IL-1B+3953 did not significantly affect periodontal parameters. Thus a central MHC gene characteristic of the 8.1 haplotype was the clearest determinant of periodontal attachment loss in HIV-infected individuals.

Adult↗