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Hollenbach J.A.,Childrens Hospital Oakland Research Institute | Meenagh A.,Immunogenetics Laboratory | Sleator C.,Immunogenetics Laboratory | Alaez C.,Secretary of Health | And 26 more authors.
Tissue Antigens | Year: 2010

The killer immunoglobulin-like receptor (KIR) anthropology component of the 15th International Histocompatibility Workshop (IHIWS) sought to explore worldwide population variation in the KIR loci, and to examine the relationship between KIR genes and their human leukocyte antigen (HLA) ligands. Fifteen laboratories submitted KIR genotype and HLA ligand data in 27 populations from six broad ethnic groups. Data were analyzed for correlations between the frequencies of KIR and their known HLA ligands. In addition, allelic typing was performed for KIR2DL2 and 3DL1 in a subset of populations. Strong and significant correlations were observed between KIR2DL2, 2DL3 genotype frequencies and the frequency of their ligand, HLA-C1. In contrast, only weak associations were seen for 3DL1, 3DS1 and the HLA-Bw4 ligand. Although some aspects of the correlations observed here differ from those reported in other populations, these data provide additional evidence of linked evolutionary histories for some KIR and HLA loci. Investigation of allele-level variation for the B haplotype locus KIR 2DL2 showed that two alleles, *001 and *003, predominate in all populations in this study. Much more allelic variation was observed for the A haplotype locus 3DL1, with several alleles observed at moderate frequencies and extensive variation observed between populations. © 2010 John Wiley & Sons A/S.


Girdlestone J.,Histocompatibility and Immunogenetics Research Group | Girdlestone J.,University College London | Pido-Lopez J.,Histocompatibility and Immunogenetics Research Group | Srivastava S.,Histocompatibility and Immunogenetics Research Group | And 7 more authors.
Cytotherapy | Year: 2015

Background aims: Multipotent mesenchymal stromal cells (MSCs) are distinguished by their ability to differentiate into a number of stromal derivatives of interest for regenerative medicine, but they also have immunoregulatory properties that are being tested in a number of clinical settings. Methods: We show that brief incubations with rapamycin, everolimus, FK506 or cyclosporine A increase the immunosuppressive potency of MSCs and other cell types. Results: The treated MSCs are up to 5-fold more potent at inhibiting the induced proliferation of T lymphocytes in vitro. We show that this effect probably is due to adsorption of the drug by the MSCs during pre-treatment, with subsequent diffusion into co-cultures at concentrations sufficient to inhibit T-cell proliferation. MSCs contain measurable amounts of rapamycin after a 15-min exposure, and the potentiating effect is blocked by a neutralizing antibody to the drug. With the use of a pre-clinical model of acute graft-versus-host disease, we demonstrate that a low dose of rapamycin-treated but not untreated umbilical cord-derived MSCs significantly inhibit the onset of disease. Conclusions: The use of treated MSCs may achieve clinical end points not reached with untreated MSCs and allow for infusion of fewer cells to reduce costs and minimize potential side effects. © 2015 International Society for Cellular Therapy.


PubMed | Royal Brompton & Harefield NHS Foundation Trust, King's College London, University College London and Histocompatibility and Immunogenetics Research Group
Type: Journal Article | Journal: Cytotherapy | Year: 2015

Multipotent mesenchymal stromal cells (MSCs) are distinguished by their ability to differentiate into a number of stromal derivatives of interest for regenerative medicine, but they also have immunoregulatory properties that are being tested in a number of clinical settings.We show that brief incubations with rapamycin, everolimus, FK506 or cyclosporine A increase the immunosuppressive potency of MSCs and other cell types.The treated MSCs are up to 5-fold more potent at inhibiting the induced proliferation of T lymphocytes in vitro. We show that this effect probably is due to adsorption of the drug by the MSCs during pre-treatment, with subsequent diffusion into co-cultures at concentrations sufficient to inhibit T-cell proliferation. MSCs contain measurable amounts of rapamycin after a 15-min exposure, and the potentiating effect is blocked by a neutralizing antibody to the drug. With the use of a pre-clinical model of acute graft-versus-host disease, we demonstrate that a low dose of rapamycin-treated but not untreated umbilical cord-derived MSCs significantly inhibit the onset of disease.The use of treated MSCs may achieve clinical end points not reached with untreated MSCs and allow for infusion of fewer cells to reduce costs and minimize potential side effects.


Powley L.,Histocompatibility and Immunogenetics Research Group | Powley L.,University College London | Brown C.,Colindale Center | Melis A.,Europdonor Foundation | And 4 more authors.
Bone Marrow Transplantation | Year: 2016

In cord blood (CB) transplantation, virtual 6/6 HLA matches, whereby the donor-recipient mismatch is identical to the CB noninherited maternal Ag (NIMA), have similar outcomes to inherited 6/6 matches. In the UK-British Bone Marrow Registry (BBMR), 4707 of the total 21 020 CB donors have the NIMA defined. Retrospective searches of these donors, for 1-3 NIMA matches, identified a virtual 6/6 match for 31.4% of 274 European Caucasoid (EC) and 25.4% of 67 other ethnicity (OE) patients. Patients weighing ≤50 kg were also evaluated for a single graft with adequate cell dose. In 125 EC patients, 6/6 HLA matches were identified for 24.0% and virtual 6/6 matches were identified for a further 21.6%. The remaining EC patients had a 5/6 (30.4%) or a 4/6 (22.4%) match. In OE patients, 6/6 HLA matches were identified for 9.3% and virtual 6/6 matches were identified for a further 18.7%. The remaining OE patients had a 5/6 (30.2%) or a 4/6 (37.2%) match. Searches were also performed using the 26 735 Bone Marrow Donors Worldwide CB with defined NIMA and yielded comparable increases. Considering NIMA as permissible mismatches in donor selection therefore increased the availability of a 6/6 match in this cohort. © 2016 Macmillan Publishers Limited.


PubMed | Colindale Center, Europdonor Foundation, Cord Blood Registry and Histocompatibility and Immunogenetics Research Group
Type: Journal Article | Journal: Bone marrow transplantation | Year: 2016

In cord blood (CB) transplantation, virtual 6/6 HLA matches, whereby the donor-recipient mismatch is identical to the CB noninherited maternal Ag (NIMA), have similar outcomes to inherited 6/6 matches. In the UK-British Bone Marrow Registry (BBMR), 4707 of the total 21020 CB donors have the NIMA defined. Retrospective searches of these donors, for 1-3 NIMA matches, identified a virtual 6/6 match for 31.4% of 274 European Caucasoid (EC) and 25.4% of 67 other ethnicity (OE) patients. Patients weighing 50kg were also evaluated for a single graft with adequate cell dose. In 125 EC patients, 6/6 HLA matches were identified for 24.0% and virtual 6/6 matches were identified for a further 21.6%. The remaining EC patients had a 5/6 (30.4%) or a 4/6 (22.4%) match. In OE patients, 6/6 HLA matches were identified for 9.3% and virtual 6/6 matches were identified for a further 18.7%. The remaining OE patients had a 5/6 (30.2%) or a 4/6 (37.2%) match. Searches were also performed using the 26735 Bone Marrow Donors Worldwide CB with defined NIMA and yielded comparable increases. Considering NIMA as permissible mismatches in donor selection therefore increased the availability of a 6/6 match in this cohort.


Shabir S.,Queen Elizabeth Hospital Birmingham | Shabir S.,University of Birmingham | Girdlestone J.,Histocompatibility and Immunogenetics Research Group | Girdlestone J.,University College London | And 16 more authors.
American Journal of Transplantation | Year: 2015

Recent cross-sectional studies suggest an important role for transitional B lymphocytes (CD19 + CD24hiCD38hi) in promoting transplant tolerance, and protecting from late antibody-mediated rejection (ABMR). However, prospective studies are lacking. This study enrolled 73 de novo transplant recipients, and collected serial clinical, immunological and biochemical information over 48 ± 6 months. Cell phenotyping was conducted immediately prior to transplantation, and then on five occasions during the first year posttransplantation. When modeled as a time-dependent covariate, transitional B cell frequencies (but not total B cells or "regulatory" T cells) were associated with protection from acute rejection (any Banff grade; HR: 0.60; 95% CI: 0.37-0.95; p = 0.03). No association between transitional B cell proportions and either de novo donor-specific or nondonor-specific antibody (dnDSA; dnNDSA) formation was evident, although preserved transitional B cell proportions were associated with reduced rejection rates in those patients developing dnDSA. Three episodes of ABMR occurred, all in the context of nonadherence, and all associated with in vitro anti-HLA T cell responses in an ELISPOT assay (p = 0.008 versus antibody-positive patients not experiencing ABMR). This prospective study supports the potential relevance of transitional ("regulatory") B cells as a biomarker and therapeutic intervention in transplantation, and highlights relationships between humoral immunity, cellular immunity and nonadherence. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.


Hunig T.,University of Würzburg | Luhder F.,University of Würzburg | Luhder F.,University of Gottingen | Elflein K.,University of Würzburg | And 6 more authors.
Medical Microbiology and Immunology | Year: 2010

The costimulatory receptor CD28 and IL-4Rα-containing cytokine receptors play key roles in controlling the size and quality of pathogen-specific immune responses. Thus, CD28-mediated costimulation is needed for effective primary T-cell expansion and for the generation and activation of regulatory T-cells (Treg cells), which protect from immunopathology. Similarly, IL-4Rα signals are required for alternative activation of macrophages, which counteract inflammation by type 1 responses. Furthermore, immune modulation by CD28 and IL-4 is interconnected through the promotion of IL-4 producing T-helper 2 cells by CD28 signals. Using conditionally IL-4Rα and CD28 deleting mice, as well as monoclonal antibodies, which block or stimulate CD28, or mAb that deplete Treg cells, we have studied the roles of CD28 and IL-4Rα in experimental mouse models of virus (influenza), intracellular bacteria (L. monocytogenes, M. tuberculosis), and parasite infections (T. congolense, L. major). We observed that in some, but not all settings, Treg cells and type 2 immune deviation, including activation of alternative macrophages can be manipulated to protect the host either from infection or from immunopathology with an overall beneficial outcome. Furthermore, we provide direct evidence that secondary CD8 T-cell responses to i.c. bacteria are dependent on CD28-mediated costimulation. © 2010 Springer-Verlag.

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