Modeling the benefits and costs of integrating an acceptable HLA mismatch allocation model for highly sensitized patients.

Background: The Eurotransplant acceptable mismatch program has improved transplantation access for highly sensitized recipients. However, the benefits and costs of implementing such a program remain unknown.

Methods: Using decision analytical modeling, we compared the average waiting time for transplantation, overall survival gains (in life-years and quality-adjusted life-years gained), and costs of integrating an acceptable mismatch allocation model compared with the current deceased-donor kidney allocation model in Australia.

Killer Ig-like receptor 2DL4 does not mediate NK cell IFN-γ responses to soluble HLA-G preparations.

The MHC class Ib molecule HLA-G has previously been reported to be the ligand for the NK cell receptor killer Ig-like receptor (KIR)2DL4, but this remains controversial. In this study, we investigated IFN-γ production by freshly isolated NK cells in response to both soluble and solid-phase ligands, including anti-KIR2DL4 mAbs and rHLA-G. Although freshly isolated CD56(bright) NK cells produced IFN-γ in response to soluble HLA-G preparations, the response was found to be absolutely dependent on the presence of small numbers of contaminating CD56(-), CD14(-), CD11c(+) myeloid dendritic cells (mDCs).

Peri-operative third party red blood cell transfusion in renal transplantation and the risk of antibody-mediated rejection and graft loss.

Historic red blood cell transfusion (RBCT) may induce anti-HLA antibody which, if donor specific (DSA), is associated with increased antibody-mediated rejection (AMR). Whether post-operative RBCT influences this risk is unknown. We examined the RBCT history in 258 renal transplant recipients stratified according to prevalent recipient HLA antibody (DSA, Non-DSA or No Antibody).

The influence of non-HLA gene polymorphisms and interactions on disease risk in a Western Australian multiple sclerosis cohort.

Non-Human Leukocyte Antigen (HLA) genes have concomitant, although modest, effects on multiple sclerosis (MS) susceptibility; however findings have varied in different populations. Here we present the results of an association study of 16 single nucleotide polymorphisms (SNPs) in 10 non-HLA genes (IL7R, IL2RA, CLEC-16A, TYK2, CD58, IRF5, STAT3, CTLA-4, APOE, ICAM-1) in a Western Australian cohort of 350 MS patients and 498 population control subjects. Our results indicate that in this population, SNPs in IL7R, TYK2, IRF5 and APOE have modifying effects on MS susceptibility.

Pre-transplant donor specific anti-HLA antibody is associated with antibody-mediated rejection, progressive graft dysfunction and patient death.

The long term effect of donor specific antibodies (DSA) detected by Luminex Single Antigen Bead (SAB) assay in the absence of a positive complement-dependant cytotoxicity (CDC) crossmatch is unclear. DSA at the time of transplant were determined retrospectively in 258 renal transplant recipients from 2003 to 2007 and their relationship with rejection and graft function prospectively evaluated. After a median of 5.

Transnational validation of the Australian algorithm for virtual crossmatch allocation in kidney paired donation.

An independent pool of 16 incompatible live donor-recipient pairs registered at the Vienna transplant unit was applied to test whether virtual crossmatch allocation used in the Australian kidney paired donation (KPD) program reliably predicts negative crossmatches. High resolution HLA data were entered into the computer-matching algorithm and allocation was performed excluding any DSA>2000MFI. CDC and flow crossmatch data of recipients against any of the donors were available for 112 crossmatch combinations.

High transplant rates of highly sensitized recipients with virtual crossmatching in kidney paired donation.

Background: In kidney paired donation (KPD), flexibility in the allocation of incompatible pairs is required if a critical mass of pairs to efficiently find matches cannot be reached.

Methods: In the Australian KPD program, virtual crossmatch is used for the allocation of suitable donors to registered recipients. Matching is based on acceptable mismatches, and donors are excluded from matching to recipients with donor-specific antibodies (DSAs) greater than 2000 mean fluorescence intensity (MFI).

Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk.

Objective: The identification of a vitamin D-responsive (VDRE) motif within the HLA-DRB1*15:01 promoter region provides an attractive explanation for the combined effects of HLA-DR inheritance and vitamin D exposure on multiple sclerosis (MS) risk. We therefore sought to incorporate HLA-DRB1 promoter variation, including the VDRE motif, in an assessment of HLA-DRB1-associated MS risk.

Methods: We utilized 32 homozygous HLA cell lines (covering 17 DRB1 alleles) and 53 heterozygote MS samples (20 DRB1 alleles) for HLA-DRB1 promoter sequencing.

The detection of NK cell alloreactivity by flow cytometric CD107a assay.

Natural killer (NK) cell alloreactivity can be exploited in haploidentical (one haplotype mismatched) haematopoietic stem cell transplantation (HSCT) to prevent leukaemia relapse, rejection, and graft-vs-host disease (GVHD) (Blood 94:333-339; Science 295:2097-2100). If NK cell alloreactivity is to be exploited in HSCT, it is important to be able to reliably select donors who have NK alloreactivity towards the patient. The detection of donor NK alloreactivity towards patient target cells has traditionally been evaluated by NK cell cloning and (51)Cr-release cytotoxicity assay.

Spinal cord involvement in multiple sclerosis: a correlative MRI and high-resolution HLA-DRB1 genotyping study.

Background: There have been few magnetic resonance imaging (MRI) studies of the spinal cord in large multiple sclerosis (MS) patient cohorts and little is known about correlations between cord lesions and human leukocyte antigen (HLA) alleles.

Objective: To investigate the spectrum of MRI changes in the spinal cord in MS and associations with the HLA-DRB1 genotype.

Methods: Two hundred and fifty two consecutive MS patients from the Perth Demyelinating Diseases Database had MRI of the spinal cord and brain and high-resolution HLA-DRB1 genotyping.

Clinical profile and HLA-DRB1 genotype of late onset multiple sclerosis in Western Australia.

We aimed to characterize the clinical profile and human leukocyte antigen (HLA)-DRB1 genotype of patients with late onset multiple sclerosis (LOMS) in Western Australia. The clinical features, laboratory studies and HLA-DRB1 alleles were analysed in patients with multiple sclerosis (MS) with onset over 50years of age and compared with 100 patients with early onset MS (EOMS). Of a cohort of 829 patients with MS, 73 (8.

HLA-DRB1 allele heterogeneity influences multiple sclerosis severity as well as risk in Western Australia.

Susceptibility to multiple sclerosis (MS) has been consistently associated with the Human Leukocyte Antigen (HLA)-DRB11501 genotype, however effects on disease severity and clinical outcome have varied in different populations. We present the results of a high-resolution HLA-DRB1 genotyping and genotype-phenotype correlation study in a large West Australian MS cohort. Our findings indicate that in this population, which is of largely Anglo-Celtic and Northern European origin, HLA-DRB11501 is not only a strong determinant of disease risk but may also be associated with disease severity as measured by the Multiple Sclerosis Severity Score (MSSS), with the MSSS increasing by an estimated 0.

Modifying effects of HLA-DRB1 allele interactions on age at onset of multiple sclerosis in Western Australia.

The contribution of genetic factors to the age at onset in multiple sclerosis is poorly understood. Our objective was to investigate the disease modifying effects of HLA-DRB1 alleles and allele interactions on age at onset of multiple sclerosis. High-resolution four-digit HLA-DRB1 genotyping was performed in a cohort of 461 multiple sclerosis patients from the Perth Demyelinating Diseases Database.

Rapid, flow cytometric assay for NK alloreactivity reveals exceptions to rules governing alloreactivity.

Alloreactive NK cells lyse target cells lacking self-HLA-C or the HLA-B-Bw4 epitope. Prior to haploidentical stem cell transplants, donor alloreactivity toward the patient is evaluated by natural killer (NK) cloning followed by testing of the clones in the (51)Cr-release assay. As only a few percent of NK clones are alloreactive, a large number of NK clones must be established and evaluated.

Presence of CSF oligoclonal bands (OCB) is associated with the HLA-DRB1 genotype in a West Australian multiple sclerosis cohort.

High-resolution HLA-DRB1 genotyping was performed in 97 OCB-positive and 68 OCB-negative cases with demyelinating disease to determine the influence of HLA-DRB1 alleles on the presence of OCB in a West Australian multiple sclerosis (MS) cohort. Carriage of the HLA-DRB1*1501 allele was associated with both OCB-positive and OCB-negative MS compared with controls, but more strongly with the OCB-positive group, and increased the likelihood of having OCB 2.1-fold with evidence of a dominant dose-effect.

Sporadic inclusion body myositis: HLA-DRB1 allele interactions influence disease risk and clinical phenotype.

Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestral haplotype (HLA-A1, B8, DRB1*03) but little is known about the effects of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. HLA-A, B and DRB1 genotyping was performed in 80 Australian sIBM cases and the frequencies of different alleles and allele combinations were compared with those in a group of 190 healthy controls.

Natural killer cell allorecognition of missing self in allogeneic hematopoietic transplantation: a tool for immunotherapy of leukemia.

Donor-versus-recipient natural killer (NK) cell alloreactivity has been established as a key therapeutic element in HLA haplotype mismatched hematopoietic transplants in adult AML and pediatric ALL and as a possible beneficial effector in cord blood transplant for AML. It is effected by functional NK cells which express inhibitory killer cell immunoglobulin-like receptor(s) (KIR) for self-class I ligand(s), sense missing expression of donor KIR ligand(s) in the recipient and mediate alloreactions. At present NK cell allotherapy for leukemia is deployed through stem cell transplantation (and ensuing NK cell reconstitution) across KIR ligand mismatches.

Allogeneic hematopoietic stem cell transplantation recipients have defects of both switched and igm memory B cells.

Allogeneic hematopoietic stem cell transplant (HSCT) recipients were assessed to elucidate memory B cell defects underlying their increased susceptibility to infections, particularly by encapsulated bacteria. Circulating IgM memory B cells (CD19+, CD27+, IgM+) and switched memory B cells (CD19+, CD27+, IgM(-)) were enumerated in allogeneic HSCT recipients (n = 37) and healthy controls (n = 35). T lymphocyte subpopulations and serum levels of immunoglobulins, including IgG subclasses, and antibodies to pneumococcal polysaccharides were also assayed.

Paired kidney donations to expand the living donor pool: the Western Australian experience.

Falling numbers of deceased organ donors and longer kidney transplant waiting lists have increased the emphasis on live kidney donation to meet demand for kidney transplantation. Several new strategies have been introduced to expand live donation beyond the classic direct donation. These include: altruistic donation; paired kidney exchange (PKE); and altruistic donor chains programs.

The reactivity of Bw4+ HLA-B and HLA-A alleles with KIR3DL1: implications for patient and donor suitability for haploidentical stem cell transplantations.

Natural killer (NK)-cell alloreactivity can be exploited in haploidentical hematopoietic stem cell transplantation (HSCT). NK cells from donors whose HLA type includes Bw4, a public epitope present on a subset of HLA-B alleles, can be alloreactive toward recipients whose cells lack Bw4. Serologically detectable epitopes related to Bw4 also exist on a subset of HLA-A alleles, but the interaction of these alleles with KIR3DL1 is controversial.

HLA antibodies and soluble CD30 are associated with poor renal graft outcome: updated results of a single-center cross-sectional study.

In a previous study, we have shown that HLA class II antibodies and a high soluble CD30 (sCD30) measured at least 1 year post-transplant predict subsequent graft failure. We have now updated the results of this same cohort of 208 patients 15 months later. HLA-specific antibodies (class I and class II) were detected by ELISA LAT-M and Luminex LabScreen assays.

Mapping MHC-resident transplantation determinants.

Graft-versus-host disease (GVHD) accounts for increased morbidity and mortality after HLA-identical unrelated hematopoietic cell transplantation (HCT). To test the hypothesis that the major histocompatibility complex (MHC) encodes functional variation other than the classical HLA genes, we measured risks associated with donor-recipient MHC microsatellite (Msat) marker mismatching in 819 HCT recipients and their HLA-A, -B, -C, -DRB1, and -DQB1 allele-matched unrelated donors. Suggestive trends of association with transplant outcome were observed for 5 Msats.