Publications by authors named "Laura Jardine"

26 Publications

  • Page 1 of 1

Blood and immune development in human fetal bone marrow and Down syndrome.

Nature 2021 10 29;598(7880):327-331. Epub 2021 Sep 29.

Wellcome Sanger Institute, Hinxton, UK.

Haematopoiesis in the bone marrow (BM) maintains blood and immune cell production throughout postnatal life. Haematopoiesis first emerges in human BM at 11-12 weeks after conception, yet almost nothing is known about how fetal BM (FBM) evolves to meet the highly specialized needs of the fetus and newborn. Here we detail the development of FBM, including stroma, using multi-omic assessment of mRNA and multiplexed protein epitope expression. We find that the full blood and immune cell repertoire is established in FBM in a short time window of 6-7 weeks early in the second trimester. FBM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time. The substantial expansion of B lymphocytes in FBM contrasts with fetal liver at the same gestational age. Haematopoietic progenitors from fetal liver, FBM and cord blood exhibit transcriptional and functional differences that contribute to tissue-specific identity and cellular diversification. Endothelial cell types form distinct vascular structures that we show are regionally compartmentalized within FBM. Finally, we reveal selective disruption of B lymphocyte, erythroid and myeloid development owing to a cell-intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in Down syndrome (trisomy 21).
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http://dx.doi.org/10.1038/s41586-021-03929-xDOI Listing
October 2021

Body mass and sex, not local climate, drive differences in chill coma recovery times in common garden reared bumble bees.

J Comp Physiol B 2021 Sep 25;191(5):843-854. Epub 2021 Jun 25.

Department of Zoology and Physiology and Program in Ecology, University of Wyoming, 1000 East University Avenue, Dept 3166, Laramie, WY, 82071, USA.

The time required to recover from cold exposure (chill coma recovery time) may represent an important metric of performance and has been linked to geographic distributions of diverse species. Chill coma recovery time (CCRT) has rarely been measured in bumble bees (genus Bombus) but may provide insights regarding recent changes in their distributions. We measured CCRT of Bombus vosnesenskii workers reared in common garden laboratory conditions from queens collected across altitude and latitude in the Western United States. We also compared CCRTs of male and female bumble bees because males are often overlooked in studies of bumble bee ecology and physiology and may differ in their ability to respond to cold temperatures. We found no relationship between CCRT and local climate at the queen collection sites, but CCRT varied significantly with sex and body mass. Because differences in the ability to recover from cold temperatures have been shown in wild-caught Bombus, we predict that variability in CCRT may be strongly influenced by plasticity.
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http://dx.doi.org/10.1007/s00360-021-01385-7DOI Listing
September 2021

Single-cell multi-omics analysis of the immune response in COVID-19.

Nat Med 2021 05 20;27(5):904-916. Epub 2021 Apr 20.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16C1QA/B/C) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34 hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8 T cells and an increased ratio of CD8 effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.
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http://dx.doi.org/10.1038/s41591-021-01329-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121667PMC
May 2021

Human lung macrophages: roll up for the MISTRG tour.

Immunity 2021 02;54(2):194-196

Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Department of Dermatology and NIHR Newcastle Biomedical Research Centre, the Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4LP, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Electronic address:

The human lung harbors diverse macrophages that provide barrier immunity and maintain homeostasis, but their precursors are unclear. In this issue of Immunity, Evren et al. use a humanized mouse model to discern that classical monocytes give rise to alveolar and interstitial macrophages, whereas non-classical monocytes contribute to pulmonary intravascular macrophages.
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http://dx.doi.org/10.1016/j.immuni.2021.01.006DOI Listing
February 2021

Developmental cell programs are co-opted in inflammatory skin disease.

Science 2021 01;371(6527)

Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital Campus, London SE1 9RT, UK.

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.
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http://dx.doi.org/10.1126/science.aba6500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611557PMC
January 2021

Donor monocyte-derived macrophages promote human acute graft-versus-host disease.

J Clin Invest 2020 09;130(9):4574-4586

Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Myelopoiesis is invariably present and contributes to pathology in animal models of graft-versus-host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties, and role in pathogenesis of these cells, we isolated single-cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome, and in vitro functional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and NanoString gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRPα and S100A8/9 transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and costimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a keratinocyte cell line and mediated pathological damage to skin explants independently of T cells. Together, these results define the origin, functional properties, and potential pathogenic roles of human GVHD macrophages.
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http://dx.doi.org/10.1172/JCI133909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456218PMC
September 2020

Prenatal development of human immunity.

Science 2020 05;368(6491):600-603

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

The blood and immune systems develop in parallel during early prenatal life. Waves of hematopoiesis separated in anatomical space and time give rise to circulating and tissue-resident immune cells. Previous observations have relied on animal models, which differ from humans in both their developmental timeline and exposure to microorganisms. Decoding the composition of the human immune system is now tractable using single-cell multi-omics approaches. Large-scale single-cell genomics, imaging technologies, and the Human Cell Atlas initiative have together enabled a systems-level mapping of the developing human immune system and its emergent properties. Although the precise roles of specific immune cells during development require further investigation, the system as a whole displays malleable and responsive properties according to developmental need and environmental challenge.
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http://dx.doi.org/10.1126/science.aaz9330DOI Listing
May 2020

Reconstructing human DC, monocyte and macrophage development in utero using single cell technologies.

Mol Immunol 2020 07 4;123:1-6. Epub 2020 May 4.

Biosciences Institute, Newcastle University, Faculty of Medical Sciences, Newcastle upon Tyne, NE2 4HH, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE2 4LP, UK. Electronic address:

The repertoire of dendritic cells (DCs), monocytes and macrophages in adult humans is diverse and we are appreciating this to a greater extent as high throughput methods, such a single-cell RNA sequencing, become widely adopted and scalable. This powerful lens of analysis is also beginning to shed light on prenatal immunology, allowing us to chart the emergence, tissue distribution and developmental regulation of DCs, monocytes and macrophages during early human life. In this review, we will integrate recent insights from studies of the developing immune system into our understanding of adult DC, monocyte and macrophage organization, illustrating where insights from early life both affirm and challenge current understanding.
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http://dx.doi.org/10.1016/j.molimm.2020.04.023DOI Listing
July 2020

Decoding human fetal liver haematopoiesis.

Nature 2019 10 9;574(7778):365-371. Epub 2019 Oct 9.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.
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http://dx.doi.org/10.1038/s41586-019-1652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861135PMC
October 2019

Lipopolysaccharide inhalation recruits monocytes and dendritic cell subsets to the alveolar airspace.

Nat Commun 2019 04 30;10(1):1999. Epub 2019 Apr 30.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Mononuclear phagocytes (MPs) including monocytes, macrophages and dendritic cells (DCs) are critical innate immune effectors and initiators of the adaptive immune response. MPs are present in the alveolar airspace at steady state, however little is known about DC recruitment in acute pulmonary inflammation. Here we use lipopolysaccharide inhalation to induce acute inflammation in healthy volunteers and examine the impact on bronchoalveolar lavage fluid and blood MP repertoire. Classical monocytes and two DC subsets (DC2/3 and DC5) are expanded in bronchoalveolar lavage fluid 8 h after lipopolysaccharide inhalation. Surface phenotyping, gene expression profiling and parallel analysis of blood indicate recruited DCs are blood-derived. Recruited monocytes and DCs rapidly adopt typical airspace-resident MP gene expression profiles. Following lipopolysaccharide inhalation, alveolar macrophages strongly up-regulate cytokines for MP recruitment. Our study defines the characteristics of human DCs and monocytes recruited into bronchoalveolar space immediately following localised acute inflammatory stimulus in vivo.
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http://dx.doi.org/10.1038/s41467-019-09913-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491485PMC
April 2019

Single-Cell Transcriptomics of Regulatory T Cells Reveals Trajectories of Tissue Adaptation.

Immunity 2019 02 5;50(2):493-504.e7. Epub 2019 Feb 5.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; Theory of Condensed Matter, Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK. Electronic address:

Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4 regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation.
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http://dx.doi.org/10.1016/j.immuni.2019.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382439PMC
February 2019

Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease.

JCI Insight 2018 03 8;3(5). Epub 2018 Mar 8.

Haematology, UCL Cancer Institute and Institute of Immunity & Transplantation, London, United Kingdom (UK).

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ-specific approaches to block immunopathology while avoiding global immune suppression.
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http://dx.doi.org/10.1172/jci.insight.97011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922296PMC
March 2018

Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation.

J Allergy Clin Immunol 2018 06 8;141(6):2234-2248. Epub 2017 Nov 8.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.

Background: The homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell (DC) and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function.

Objective: We sought to describe the effect on hematopoiesis and immunity of the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient with recurrent viral infection, granuloproliferation, and intracerebral calcification.

Methods: Variant IRF8 alleles were identified by means of exome sequencing, and their function was tested by using reporter assays. The cellular phenotype was studied in detail by using flow cytometry, functional immunologic assay transcriptional profiling, and antigen receptor profiling.

Results: Both mutations affected conserved residues, and R291Q is orthologous to R294, which is mutated in the BXH2 IRF8-deficient mouse. R83C showed reduced nuclear translocation, and neither mutant was able to regulate the Ets/IRF composite element or interferon-stimulated response element, whereas R291Q retained BATF/JUN interactions. DC deficiency and monocytopenia were observed in blood, dermis, and lung lavage fluid. Granulocytes were consistently increased, dysplastic, and hypofunctional. Natural killer cell development and maturation were arrested. T1, T17, and CD8 memory T-cell differentiation was significantly reduced, and T cells did not express CXCR3. B-cell development was impaired, with fewer memory cells, reduced class-switching, and lower frequency and complexity of somatic hypermutation. Cell-specific gene expression was widely disturbed in interferon- and IRF8-regulated transcripts.

Conclusions: This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation.
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http://dx.doi.org/10.1016/j.jaci.2017.08.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986711PMC
June 2018

Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors.

Science 2017 04;356(6335)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease.
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http://dx.doi.org/10.1126/science.aah4573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775029PMC
April 2017

Impact of Alemtuzumab Scheduling on Graft-versus-Host Disease after Unrelated Donor Fludarabine and Melphalan Allografts.

Biol Blood Marrow Transplant 2017 May 14;23(5):805-812. Epub 2017 Feb 14.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Northern Centre for Bone Marrow Transplantation, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom. Electronic address:

Alemtuzumab conditioning is highly effective at reducing the incidence of acute and chronic graft-versus-host disease (GVHD) in reduced-intensity fludarabine and melphalan transplantation with cyclosporine monotherapy. Less frequent and lower dose scheduling may be used with sibling donors, but an optimal regimen for matched unrelated donors has not been defined. In this retrospective observational study of 313 patients, the incidence and severity of GVHD was compared in patients receiving 3 different dose schedules: the standard 100-mg regimen (20 mg on days -7 to -3), 60 mg (30 mg on days -4 and -2), or 50 mg (10 mg on days -7 to -3). Patients treated with 100 mg, 60 mg, or 50 mg developed acute GVHD grades I to IV with an incidence of 74%, 65%, and 64%, respectively, whereas 36%, 32%, and 41% developed chronic GHVD. An excess of severe acute grades III/IV GVHD was observed in the 50-mg cohort (15% versus 2% to 6%; P = .016). The relative risk of severe acute grade GVHD remained more than 3-fold higher in the 50-mg cohort compared with the 100-mg cohort after adjustment for differences in HLA match, age, gender mismatch, cytomegalovirus risk, and diagnosis (P = .030). The findings indicate that the 60-mg alemtuzumab schedule was comparable with the 100-mg schedule, but more attenuated schedules may increase the risk of severe grade GVHD.
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http://dx.doi.org/10.1016/j.bbmt.2017.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588535PMC
May 2017

Isolation of Human Skin Dendritic Cell Subsets.

Methods Mol Biol 2016 ;1423:119-28

Human DC Lab, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Dendritic cells (DCs) are specialized leukocytes with antigen-processing and antigen-presenting functions. DCs can be divided into distinct subsets by anatomical location, phenotype and function. In human, the two most accessible tissues to study leukocytes are peripheral blood and skin. DCs are rare in human peripheral blood (<1 % of mononuclear cells) and have a less mature phenotype than their tissue counterparts (MacDonald et al., Blood. 100:4512-4520, 2002; Haniffa et al., Immunity 37:60-73, 2012). In contrast, the skin covering an average total surface area of 1.8 m(2) has approximately tenfold more DCs than the average 5 L of total blood volume (Wang et al., J Invest Dermatol 134:965-974, 2014). DCs migrate spontaneously from skin explants cultured ex vivo, which provide an easy method of cell isolation (Larsen et al., J Exp Med 172:1483-1493, 1990; Lenz et al., J Clin Invest 92:2587-2596, 1993; Nestle et al., J Immunol 151:6535-6545, 1993). These factors led to the extensive use of skin DCs as the "prototype" migratory DCs in human studies. In this chapter, we detail the protocols to isolate DCs and resident macrophages from human skin. We also provide a multiparameter flow cytometry gating strategy to identify human skin DCs and to distinguish them from macrophages.
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http://dx.doi.org/10.1007/978-1-4939-3606-9_8DOI Listing
December 2017

A comparative study of reduced dose alemtuzumab in matched unrelated donor and related donor reduced intensity transplants.

Br J Haematol 2015 Mar 29;168(6):874-81. Epub 2015 Jan 29.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

In vivo T cell depletion with 100 mg alemtuzumab prevents graft-versus-host disease (GVHD) in reduced intensity conditioned transplants but is associated with delayed immune reconstitution, a higher risk of infection and relapse. De-escalation studies have shown that a reduced dose of 30 mg is as effective as 100 mg in preventing GVHD in matched related donor (MRD) transplants. Dose reduction in matched unrelated donor (MUD) transplants is feasible but the comparative efficacy of alemtuzumab in this setting is not known and opinions vary widely concerning the optimal level of GVHD prophylaxis that should be achieved. Through retrospective analysis we made an objective comparison of MUD transplants receiving an empirically reduced dose of 60 mg, with MRD transplants receiving a 30 mg dose. We observed proportionate levels of alemtuzumab according to dose but an inverse relationship with body surface area particularly in MRD transplants. MUD transplants experienced more acute and chronic GVHD, higher T cell chimerism, more sustained use of ciclosporin and less need for donor lymphocyte infusion than MRD transplants. Thus, doubling the dose of alemtuzumab to 60 mg did not provide equivalent prevention of GVHD after MUD transplant although there was no difference in non-relapse mortality or survival compared with MRD transplants.
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http://dx.doi.org/10.1111/bjh.13239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737113PMC
March 2015

Human skin dendritic cells in health and disease.

J Dermatol Sci 2015 Feb 10;77(2):85-92. Epub 2014 Sep 10.

Institute of Cellular Medicine, Newcastle University, NE2 4HH, UK.

Dendritic cells (DCs) are specialized antigen presenting cells abundant in peripheral tissues such as skin where they function as immune sentinels. Skin DCs migrate to draining lymph node where they interact with naïve T cells to induce immune responses to microorganisms, vaccines, tumours and self-antigens. In this review, we present the key historical developments and recent advances in human skin DC research. We also integrate the current understanding on the origin and functional specializations of DC subsets in healthy skin with findings in inflammatory skin diseases focusing on psoriasis and atopic eczema. A comprehensive understanding of the dynamic changes in DC subsets in health and disease will form a strong foundation to facilitate the clinical translation of DC-based therapeutic and vaccination strategies.
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http://dx.doi.org/10.1016/j.jdermsci.2014.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728191PMC
February 2015

Human dermal CD14⁺ cells are a transient population of monocyte-derived macrophages.

Immunity 2014 Sep 4;41(3):465-477. Epub 2014 Sep 4.

Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. Electronic address:

Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1⁺ CLEC9A⁺ DCs and CD1c⁺ DCs are murine CD103⁺ DCs and CD64⁻ CD11b⁺ DCs. In addition, human tissues also contain CD14⁺ cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14⁺ cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14⁺ monocytes and dermal CD14⁺ cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14⁺ cells are CD11b⁺ CD64⁺ monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system.
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http://dx.doi.org/10.1016/j.immuni.2014.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175180PMC
September 2014

A question of persistence: Langerhans cells and graft-versus-host disease.

Exp Dermatol 2014 Apr;23(4):234-5

Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

Langerhans cells (LCs) have been scrutinized many times in studies of the pathogenesis of graft-versus-host disease (GVHD). As migratory dendritic cells, LCs are capable of direct antigen presentation to cytotoxic T cells. Their self-renewal capacity has led to speculation that persistent recipient LCs could provide a continuous source of host antigen to donor T cells infused during hematopoietic stem cell transplantation (HSCT). In this issue of Experimental Dermatology, a new study examines at the relationship between recipient LCs and chronic GVHD.
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http://dx.doi.org/10.1111/exd.12325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150527PMC
April 2014

Rapid detection of dendritic cell and monocyte disorders using CD4 as a lineage marker of the human peripheral blood antigen-presenting cell compartment.

Front Immunol 2013 27;4:495. Epub 2013 Dec 27.

Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK.

Dendritic cells (DCs) and monocytes are critical regulators and effectors of innate and adaptive immune responses. Monocyte expansion has been described in many pathological states while monocyte and DC deficiency syndromes are relatively recent additions to the catalog of human primary immunodeficiency disorders. Clinically applicable screening tests to diagnose and monitor these conditions are lacking. Conventional strategies for identifying human DCs and monocytes have been based on the use of a lineage gate to exclude lymphocytes, thus preventing simultaneous detection of DCs, monocytes, and lymphocyte subsets. Here we demonstrate that CD4 is a reliable lineage marker for the human peripheral blood antigen-presenting cell compartment that can be used to identify DCs and monocytes in parallel with lymphocytes. Based on this principle, simple modification of a standard lymphocyte phenotyping assay permits simultaneous enumeration of four lymphocyte and five DC/monocyte populations from a single sample. This approach is applicable to clinical samples and facilitates the diagnosis of DC and monocyte disorders in a wide range of clinical settings, including genetic deficiency, neoplasia, and inflammation.
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http://dx.doi.org/10.3389/fimmu.2013.00495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873601PMC
January 2014

The evolution of cellular deficiency in GATA2 mutation.

Blood 2014 Feb 17;123(6):863-74. Epub 2013 Dec 17.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;

Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.
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http://dx.doi.org/10.1182/blood-2013-07-517151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916878PMC
February 2014

IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses.

Immunity 2013 May;38(5):970-83

Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 138648 Singapore.

Mouse and human dendritic cells (DCs) are composed of functionally specialized subsets, but precise interspecies correlation is currently incomplete. Here, we showed that murine lung and gut lamina propria CD11b+ DC populations were comprised of two subsets: FLT3- and IRF4-dependent CD24(+)CD64(-) DCs and contaminating CSF-1R-dependent CD24(-)CD64(+) macrophages. Functionally, loss of CD24(+)CD11b(+) DCs abrogated CD4+ T cell-mediated interleukin-17 (IL-17) production in steady state and after Aspergillus fumigatus challenge. Human CD1c+ DCs, the equivalent of murine CD24(+)CD11b(+) DCs, also expressed IRF4, secreted IL-23, and promoted T helper 17 cell responses. Our data revealed heterogeneity in the mouse CD11b+ DC compartment and identifed mucosal tissues IRF4-expressing DCs specialized in instructing IL-17 responses in both mouse and human. The demonstration of mouse and human DC subsets specialized in driving IL-17 responses highlights the conservation of key immune functions across species and will facilitate the translation of mouse in vivo findings to advance DC-based clinical therapies.
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http://dx.doi.org/10.1016/j.immuni.2013.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666057PMC
May 2013

Sensitizing primary acute lymphoblastic leukemia to natural killer cell recognition by induction of NKG2D ligands.

Leuk Lymphoma 2013 Jan 8;54(1):167-73. Epub 2012 Sep 8.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

Natural killer (NK) cell immunosurveillance may be impaired by malignant disease, resulting in tumor escape and disease progression. Therapies that enhance NK cytotoxicity may therefore prove valuable in remission-induction and maintenance treatment regimens. Acute lymphoblastic leukemia (ALL) has previously been considered resistant to NK cell lysis and not tractable to this approach. Our study demonstrates that bortezomib, valproate and troglitazone can up-regulate NK activating ligands on a B-ALL cell line and on a proportion but not all adult primary B-ALL samples. Drug-treated ALL cells trigger higher levels of NK degranulation, as measured by CD107a expression, and this effect is dependent on signaling through the NK activating receptor NKG2D. These results suggest that bortezomib, valproate and troglitazone may have clinical utility in sensitizing ALL to NK mediated lysis in vivo.
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http://dx.doi.org/10.3109/10428194.2012.708026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588533PMC
January 2013

The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency.

J Exp Med 2011 Feb 17;208(2):227-34. Epub 2011 Jan 17.

Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, England, UK.

Congenital or acquired cellular deficiencies in humans have the potential to reveal much about normal hematopoiesis and immune function. We show that a recently described syndrome of monocytopenia, B and NK lymphoid deficiency additionally includes the near absence of dendritic cells. Four subjects showed severe depletion of the peripheral blood HLA-DR(+) lineage(-) compartment, with virtually no CD123(+) or CD11c(+) dendritic cells (DCs) and very few CD14(+) or CD16(+) monocytes. The only remaining HLA-DR(+) lineage(-) cells were circulating CD34(+) progenitor cells. Dermal CD14(+) and CD1a(+) DC were also absent, consistent with their dependence on blood-derived precursors. In contrast, epidermal Langerhans cells and tissue macrophages were largely preserved. Combined loss of peripheral DCs, monocytes, and B and NK lymphocytes was mirrored in the bone marrow by complete absence of multilymphoid progenitors and depletion of granulocyte-macrophage progenitors. Depletion of the HLA-DR(+) peripheral blood compartment was associated with elevated serum fms-like tyrosine kinase ligand and reduced circulating CD4(+)CD25(hi)FoxP3(+) T cells, supporting a role for DC in T reg cell homeostasis.
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http://dx.doi.org/10.1084/jem.20101459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039861PMC
February 2011
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