Histocompatibility and Immunogenetics Laboratory

Birmingham, United Kingdom

Histocompatibility and Immunogenetics Laboratory

Birmingham, United Kingdom
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Flint S.M.,Immunoinflammation TAU | Flint S.M.,University of Cambridge | Gibson A.,Immunoinflammation TAU | Lucas G.,Histocompatibility and Immunogenetics Laboratory | And 6 more authors.
Haematologica | Year: 2016

Primary immune thrombocytopenia is an autoimmune disorder in which platelet destruction is a consequence of both B-and T-cell dysregulation. Flow cytometry was used to further characterize the B- and T-cell compartments in a cross-sectional cohort of 26 immune thrombocytopenia patients including antiplatelet antibody positive (n=14) and negative (n=12) patients exposed to a range of therapies, and a cohort of matched healthy volunteers. Markers for B-cell activating factor and its receptors, relevant B-cell activation markers (CD95 and CD21) and markers for CD4+ T-cell subsets, including circulating T-follicular helper-like cells, were included. Our results indicate that an expanded population of CD95+ naïve B cells correlated with disease activity in immune thrombocytopenia patients regardless of treatment status. A population of CD21- naïve B cells was specifically expanded in autoantibody-positive immune thrombocytopenia patients. Furthermore, the B-cell maturation antigen, a receptor for B-cell activating factor, was consistently and strongly up-regulated on plasmablasts from immune thrombocytopenia patients. These observations have parallels in other autoantibody-mediated diseases and suggest that loss of peripheral tolerance in naïve B cells may be an important component of immune thrombocytopenia pathogenesis. Moreover, the B-cell maturation antigen represents a potential target for plasma cell directed therapies in immune thrombocytopenia. © 2016 Ferrata Storti Foundation.


Lowe D.,Histocompatibility and Immunogenetics Laboratory | Lowe D.,University of Warwick | Higgins R.,Coventry University | Zehnder D.,University of Warwick | And 2 more authors.
Human Immunology | Year: 2013

IgG subclasses differ in their ability to fix complement and bind Fc receptors. This study describes a detailed analysis of the distribution of HLA-specific IgG subclasses in order to define how this varies in sensitised waiting-list patients. We found significant variation in the level, presence and combinations of each HLA-specific IgG subclass between and within individuals and this is influenced by the type of sensitising event. Graft failure in particular provokes higher levels of IgG1 (vs transfusion, p=. 0.071 and pregnancy, p=. 0.042), IgG2 (vs transfusion, p=. 0.001 and pregnancy, p=. 0.016), and IgG4 (vs transfusion, p=. 0.052). Both graft failure and pregnancy tend to stimulate multiple IgG subclass responses against HLA, whereas transfusion stimulated antibodies are dominated by responses limited to IgG1 (. p=. 0.033) and have a low incidence of IgG4 (. p=. 0.046). In marked contrast, IgG4 characterised nearly all HLA DQ-specific antibodies stimulated by graft rejection (. p=. 0.006). Such widely varying IgG subclass heterogeneity is likely to be due to underlying immunological processes dependent on the route of sensitisation. This diversity, which implies functional variation, may help explain why HLA-specific antibodies are an obstacle to transplantation in some circumstances but not others. The subclass association with rejection has potential as a biomarker for chronic rejection. © 2013 .


Clark J.R.,Sheffield Teaching Hospitals NHS Foundation Trust | Scott S.D.,Sheffield Teaching Hospitals NHS Foundation Trust | Jack A.L.,Sheffield Teaching Hospitals NHS Foundation Trust | Lee H.,Royal Infirmary | And 13 more authors.
British Journal of Haematology | Year: 2015

Analysis of short tandem repeats (STR) is the predominant method for post-transplant monitoring of donor engraftment. It can enable early detection of disease relapse, level of engraftment and provide useful information on the graft-versus-host disease (GVHD)/graft-versus-tumour (GVT) effect, facilitating therapeutic intervention. Harmonization and standardization of techniques and result interpretation is essential to reduce the impact of laboratory variability on both clinical management and the results of multi-centre clinical trials. However, the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI) has highlighted significant issues inherent in STR testing that impact upon inter- and intra- laboratory variation. We present here consensus best practice guidelines and recommendations for STR chimerism testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 11 UK and Eire clinical laboratories. This document uses data obtained from the UK NEQAS LI Post-Stem Cell Transplant (SCT) Chimerism Monitoring Programme. © 2014 John Wiley & Sons Ltd.


Sinha D.,Coventry University | Lambie M.,Coventry University | Krishnan N.,Coventry University | Mcsorley K.,Coventry University | And 7 more authors.
Therapeutic Apheresis and Dialysis | Year: 2012

Cryofiltration is a technique in which plasma is separated from blood and chilled, leading to the formation of "cryogel", a composite of heparin, fibronectin, fibrinogen, immunoglobulins, and other proteins. This is retained by further filtration and plasma is returned to the patient. There may be a role for cryofiltration in the treatment of cryoglobulinemia or where the application of other forms of plasmapheresis or immunoadsorption is limited. Five patients received six courses of cryofiltration. Two patients had cryoglobulinemia and three were treated before HLA antibody-incompatible renal transplantation. The treatment was associated with few adverse effects, and it was possible to treat up to 120mL/kg plasma per session. There was a good clinical response in four patients. One patient was switched back to double filtration plasmapheresis (DFPP) because cryofiltration seemed to remove HLA antibodies less effectively, but the other two transplants have excellent function. In the cryoglobulinemia patients there was excellent clearance of cryoglobulins during each treatment (mean decrease of 78.2 (SD 14.1)% per treatment). Compared with DFPP, fewer immunoglobulins were removed and the mean percentage reductions in immunoglobulinG per treatment were 36.0 (4.0)% for cryoglobulinemia and 59.2 (2.5)% for DFPP (P<0.01), with respective mean plasma volumes of 64.2 (10.3) and 71.1 (6.8)mL/kg treated. Cryofiltration offers a treatment choice in patients with cryoglobulinemia and in those who may not be able to tolerate high-volume DFPP. The technique used in the patients described here was less effective than DFPP; however, use of an alternative fractionator and treatment of higher plasma volumes may enhance the efficiency of cryofiltration. © 2011 The Authors. Therapeutic Apheresis and Dialysis © 2011 International Society for Apheresis.


Little A.-M.,Gartnavel General Hospital | Little A.-M.,University of Glasgow | Green A.,Histocompatibility and Immunogenetics Laboratory | Harvey J.,Histocompatibility and Immunogenetics Laboratory | And 6 more authors.
International Journal of Immunogenetics | Year: 2016

A review of the British Society for Histocompatibility and Immunogenetics (BSHI) “Guideline for selection and HLA matching of related, adult unrelated donors and umbilical cord units for haematopoietic progenitor cell transplantation” was undertaken by a BSHI appointed writing committee. Literature searches were performed, and the data extracted were presented as recommendations according to the GRADE nomenclature. © 2016 John Wiley & Sons Ltd


PubMed | Gartnavel General Hospital, Royal Infirmary, Royal Free Hospital and Histocompatibility and Immunogenetics Laboratory
Type: Journal Article | Journal: International journal of immunogenetics | Year: 2016

A review of the British Society for Histocompatibility and Immunogenetics (BSHI) Guideline for selection and HLA matching of related, adult unrelated donors and umbilical cord units for haematopoietic progenitor cell transplantation was undertaken by a BSHI appointed writing committee. Literature searches were performed, and the data extracted were presented as recommendations according to the GRADE nomenclature.


Brooks A.M.S.,Northumbria University | Carter V.,Histocompatibility and Immunogenetics Laboratory | Liew A.,Northumbria University | Marshall H.,Northumbria University | And 5 more authors.
American Journal of Transplantation | Year: 2015

Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed-meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1-3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post-first transplant; two post-second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C-peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300-1090); DSA positive 106(34-235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03). Through prospective follow up of a single-center cohort of pancreatic islet transplant recipients, the authors demonstrate that development of de novo donor-specific antibodies occurs rapidly after the sensitizing transplant and is absolutely associated with graft loss at 12 months. © 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.


Chong W.,Histocompatibility and Immunogenetics Laboratory | Chong W.,Public Health England | Chong W.,International Blood Group Reference Laboratory IBGRL | Chong W.,University of Cambridge | And 27 more authors.
Transfusion | Year: 2011

BACKGROUND: Testing for alloantibodies against human platelet antigens (HPAs) is essential for the clinical diagnosis of fetomaternal alloimmune thrombocytopenia (FMAIT), posttransfusion purpura, and platelet (PLT) refractoriness. Most of the methods currently used for HPA alloantibody detection rely on the availability of panels of HPA-typed PLTs and some rely on validated monoclonal antibodies (MoAbs) against the PLT glycoproteins. Recombinant β3 integrins displaying the HPA-1a (rHPA-1a) or HPA-1b (rHPA-1b) epitopes have been produced as an alternative source of antigen. The suitability of these integrin fragments was evaluated for the development of an HPA-1a alloantibody screening assay, using Luminex xMAP technology. STUDY DESIGN AND METHODS: A 3-plex bead assay was developed by coupling biotinylated rHPA-1a, rHPA-1b, and recombinant glycoprotein VI to LumAvidin microspheres. Forty patient samples referred for FMAIT diagnostic testing, which were previously screened by the MoAb-specific immobilization of PLT antigens (MAIPA) assay, were used to assess the assay. RESULTS: The rHPA-1a- and rHPA-1b-coupled beads were able to detect HPA-1a and HPA-1b alloantibodies in all patient samples tested that were previously confirmed to contain HPA-1-specific antibodies. Furthermore, HLA Class I antibodies did not cross-react with the coupled beads. CONCLUSION: The 3-plex bead assay can be used to detect HPA-1a antibodies with sufficient specificity and sensitivity for use in the clinical setting of FMAIT. The development of other recombinant integrin fragments with the use of Luminex xMAP technology may assist in providing more rapid HPA antibody detection, enabling prompt diagnosis of alloimmune PLT disorders. © 2010 American Association of Blood Banks.


Prevosto C.,University of Cambridge | Usmani M.F.,University of Cambridge | McDonald S.,University of Cambridge | Gumienny A.M.,University of Cambridge | And 8 more authors.
PLoS ONE | Year: 2016

Major histocompatibility complex class I (MHCI) glycoproteins present cytosolic peptides to CD8+ T cells and regulate NK cell activity. Their heavy chains (HC) are expressed from up to three MHC gene loci (human leukocyte antigen [HLA]-A, -B, and -C in humans), whose extensive polymorphism maps predominantly to the antigen-binding groove, diversifying the bound peptide repertoire. Codominant expression of MHCI alleles is thus functionally critical, but how it is regulated is not fully understood. Here, we have examined the effect of polymorphism on the turnover rates of MHCI molecules in cell lines with functional MHCI peptide loading pathways and in monocyte-derived dendritic cells (MoDCs). Proteins were labeled biosynthetically with heavy water (2H2O), folded MHCI molecules immunoprecipitated, and tryptic digests analysed by mass spectrometry. MHCI-derived peptides were assigned to specific alleles and isotypes, and turnover rates quantified by 2H incorporation, after correcting for cell growth. MHCI turnover half-lives ranged from undetectable to a few hours, depending on cell type, activation state, donor, and MHCI isotype. However, in all settings, the turnover half-lives of alleles of the same isotype were similar. Thus, MHCI protein turnover rates appear to be allele-independent in normal human cells. We propose that this is an important feature enabling the normal function and codominant expression of MHCI alleles. © 2016 Prevosto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


PubMed | Freeman Hospital, Northumbria University and Histocompatibility and Immunogenetics Laboratory
Type: Clinical Trial | Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons | Year: 2015

Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed-meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1-3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post-first transplant; two post-second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C-peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300-1090); DSA positive 106(34-235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03).

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