Publications by authors named "Joanne L Jones"

30 Publications

  • Page 1 of 1

Detection limit of Zr-labeled T cells for cellular tracking: an in vitro imaging approach using clinical PET/CT and PET/MRI.

EJNMMI Res 2020 Jul 14;10(1):82. Epub 2020 Jul 14.

Department of Radiology, University of Cambridge, Cambridge, UK.

Purpose: Tracking cells in vivo using imaging can provide non-invasive information to understand the pharmacology, efficacy, and safety of novel cell therapies. Zirconium-89 (t = 78.4 h) has recently been used to synthesize [Zr]Zr(oxinate) for cell tracking using positron emission tomography (PET). This work presents an in vitro approach to estimate the detection limit for in vivo PET imaging of Jurkat T cells directly labeled with [Zr]Zr(oxinate) utilizing clinical PET/CT and PET/MRI.

Methods: Jurkat T cells were labeled with varying concentrations of [Zr]Zr(oxinate) to generate different cell-specific activities (0.43-31.91 kBq/10 cells). Different concentrations of labeled cell suspensions (10, 10, and 10 cells) were seeded on 6-well plates and into a 3 × 3 cubic-well plate with 1 cm cubic wells as a gel matrix. Plates were imaged on clinical PET/CT and PET/MRI scanners for 30 min. The total activity in each well was determined by drawing volumes of interest over each well on PET images. The total cell-associated activity was measured using a well counter and correlated with imaging data. Simulations for non-specific signal were performed to model the effect of non-specific radioactivity on detection.

Results: Using this in vitro model, the lowest cell number that could be visualized on 6-well plate images was 6.8 × 10, when the specific activity was 27.8 kBq/10 cells. For the 3 × 3 cubic-well, a plate of 3.3 × 10 cells could be detected on images with a specific activity of 15.4 kBq/10 cells.

Conclusion: The results show the feasibility of detecting [Zr]Zr(oxinate)-labeled Jurkat T cells on clinical PET systems. The results provide a best-case scenario, as in vivo detection using PET/CT or PET/MRI will be affected by cell number, specific activity per cell, the density of cells within the target volume, and non-specific signal. This work has important implications for cell labeling studies in patients, particularly when using radiosensitive cells (e.g., T cells), which require detection of low cell numbers while minimizing radiation dose per cell.
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http://dx.doi.org/10.1186/s13550-020-00667-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360010PMC
July 2020

Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis.

Genome Med 2020 06 24;12(1):55. Epub 2020 Jun 24.

Nuffield Department of Medicine, JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.

Background: Traditionally, the transcriptomic and proteomic characterisation of CD4 T cells at the single-cell level has been performed by two largely exclusive types of technologies: single-cell RNA sequencing (scRNA-seq) and antibody-based cytometry. Here, we present a multi-omics approach allowing the simultaneous targeted quantification of mRNA and protein expression in single cells and investigate its performance to dissect the heterogeneity of human immune cell populations.

Methods: We have quantified the single-cell expression of 397 genes at the mRNA level and up to 68 proteins using oligo-conjugated antibodies (AbSeq) in 43,656 primary CD4 T cells isolated from the blood and 31,907 CD45 cells isolated from the blood and matched duodenal biopsies. We explored the sensitivity of this targeted scRNA-seq approach to dissect the heterogeneity of human immune cell populations and identify trajectories of functional T cell differentiation.

Results: We provide a high-resolution map of human primary CD4 T cells and identify precise trajectories of Th1, Th17 and regulatory T cell (Treg) differentiation in the blood and tissue. The sensitivity provided by this multi-omics approach identified the expression of the B7 molecules CD80 and CD86 on the surface of CD4 Tregs, and we further demonstrated that B7 expression has the potential to identify recently activated T cells in circulation. Moreover, we identified a rare subset of CCR9 T cells in the blood with tissue-homing properties and expression of several immune checkpoint molecules, suggestive of a regulatory function.

Conclusions: The transcriptomic and proteomic hybrid technology described in this study provides a cost-effective solution to dissect the heterogeneity of immune cell populations at extremely high resolution. Unexpectedly, CD80 and CD86, normally expressed on antigen-presenting cells, were detected on a subset of activated Tregs, indicating a role for these co-stimulatory molecules in regulating the dynamics of CD4 T cell responses.
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http://dx.doi.org/10.1186/s13073-020-00756-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315544PMC
June 2020

Severe paradoxical disease activation following alemtuzumab treatment for multiple sclerosis.

Neurol Neuroimmunol Neuroinflamm 2020 09 10;7(5). Epub 2020 Jun 10.

From Jesus College (J.B., S.R.L.S.), Cambridge University, UK; Department of Neurology (J.L.J., S.R.L.S.), Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; and Department of Neurology (S.R.L.S.), Peterborough City Hospital, North West Anglia NHS Foundation Trust, Peterborough, UK.

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http://dx.doi.org/10.1212/NXI.0000000000000799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309519PMC
September 2020

Distinct microbial and immune niches of the human colon.

Nat Immunol 2020 03 17;21(3):343-353. Epub 2020 Feb 17.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

Gastrointestinal microbiota and immune cells interact closely and display regional specificity; however, little is known about how these communities differ with location. Here, we simultaneously assess microbiota and single immune cells across the healthy, adult human colon, with paired characterization of immune cells in the mesenteric lymph nodes, to delineate colonic immune niches at steady state. We describe distinct helper T cell activation and migration profiles along the colon and characterize the transcriptional adaptation trajectory of regulatory T cells between lymphoid tissue and colon. Finally, we show increasing B cell accumulation, clonal expansion and mutational frequency from the cecum to the sigmoid colon and link this to the increasing number of reactive bacterial species.
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http://dx.doi.org/10.1038/s41590-020-0602-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212050PMC
March 2020

Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson's disease.

Brain Behav Immun 2020 07 30;87:473-488. Epub 2020 Jan 30.

John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.

The innate immune system is implicated in Parkinson's disease (PD), but peripheral in-vivo clinical evidence of the components and driving mechanisms involved and their relationship with clinical heterogeneity and progression to dementia remain poorly explored. We examined changes in peripheral innate immune-related markers in PD cases (n = 41) stratified according to risk of developing early dementia. 'Higher Risk'(HR) (n = 23) and 'Lower Risk' (LR) (n = 18) groups were defined according to neuropsychological predictors and MAPT H1/H2 genotype, and compared to age, gender and genotype-matched controls. Monocyte subsets and expression of key surface markers were measured using flow cytometry. Serum markers including alpha-synuclein, inflammasome-related caspase-1 and bacterial translocation-related endotoxin were measured using quantitative immuno-based assays. Specific markers were further investigated using monocyte assays and validated in plasma samples from a larger incident PD cohort (n = 95). We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the HR group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were also increased. Monocyte Human Leukocyte Antigen (HLA)-DR expression correlated with clinical variables, with lower levels associated with worse cognitive/motor performance. Notably, monocyte changes were accompanied by elevated serum bacterial endotoxin, again predominantly in the HR group. Serum alpha-synuclein and inflammasome-related caspase-1 were decreased in PD cases compared to controls regardless of group, with decreased monocyte alpha-synuclein secretion in HR cases. Further, alpha-synuclein and caspase-1 correlated positively in serum and monocyte lysates, and in plasma from the larger cohort, though no associations were seen with baseline or 36-month longitudinal clinical data. Principal Components Analysis of all monocyte and significant serum markers indicated 3 major components. Component 1 (alpha-synuclein, caspase-1, TLR2+ monocytes) differentiated PD cases and controls in both groups, while Component 2 (endotoxin, monocyte TREM2, alpha-synuclein) did so predominantly in the HR group. Component 3 (classical monocytes, alpha-synuclein) also differentiated cases and controls overall in both groups. These findings demonstrate that systemic innate immune changes are present in PD and are greatest in those at higher risk of rapid progression to dementia. Markers associated with PD per-se (alpha-synuclein, caspase-1), differ from those related to cognitive progression and clinical heterogeneity (endotoxin, TREM2, TLR4, classical monocytes, HLA-DR), with mechanistic and therapeutic implications. Alpha-synuclein and caspase-1 are associated, suggesting inflammasome involvement common to all PD, while bacterial translocation associated changes may contribute towards progression to Parkinson's dementia. Additionally, HLA-DR-associated variations in antigen presentation/clearance may modulate existing clinical disease.
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http://dx.doi.org/10.1016/j.bbi.2020.01.018DOI Listing
July 2020

Periventricular magnetisation transfer ratio abnormalities in multiple sclerosis improve after alemtuzumab.

Mult Scler 2020 08 6;26(9):1093-1101. Epub 2019 Jun 6.

NMR Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK; National Institute for Health Research (NIHR), University College London Hospitals (UCLH) Biomedical Research Centre, London, UK.

Background: In multiple sclerosis (MS), disease effects on magnetisation transfer ratio (MTR) increase towards the ventricles. This periventricular gradient is evident shortly after first symptoms and is independent of white matter lesions.

Objective: To explore if alemtuzumab, a peripherally acting disease-modifying treatment, modifies the gradient's evolution, and whether baseline gradients predict on-treatment relapses.

Methods: Thirty-four people with relapsing-remitting MS underwent annual magnetic resonance imaging (MRI) scanning (19 receiving alemtuzumab (four scans each), 15 untreated (three scans each)). The normal-appearing white matter was segmented into concentric bands. Gradients were measured over the three bands nearest the ventricles. Mixed-effects models adjusted for age, gender, relapse rate, lesion number and brain parenchymal fraction compared the groups' baseline gradients and evolution.

Results: Untreated, the mean MTR gradient increased (+0.030 pu/band/year) but decreased following alemtuzumab (-0.045 pu/band/year,  = 0.037). Within the alemtuzumab group, there were no significant differences in baseline lesion number ( = 0.568) nor brain parenchymal fraction ( = 0.187) between those who relapsed within 4 years ( = 4) and those who did not ( = 15). However, the baseline gradient was significantly different ( = 0.020).

Conclusion: Untreated, abnormal periventricular gradients worsen with time, but appear reversible with peripheral immunotherapy. Baseline gradients - but not lesion loads or brain volumes - may predict on-treatment relapses. Larger confirmatory studies are required.
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http://dx.doi.org/10.1177/1352458519852093DOI Listing
August 2020

Keratinocyte growth factor impairs human thymic recovery from lymphopenia.

JCI Insight 2019 05 7;5. Epub 2019 May 7.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.

Background: The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates.

Methods: Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signal-joint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30.

Findings: At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107/L vs. 7.733x107/L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocol-defined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groupsConclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime.

Trial Registration: ClinicalTrials.gov NCT01712945Funding: MRC and Moulton Charitable Foundation.
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http://dx.doi.org/10.1172/jci.insight.125377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629095PMC
May 2019

A case of anaphylaxis to alemtuzumab.

J Neurol 2019 Mar 4;266(3):780-781. Epub 2019 Feb 4.

Department of Clinical Neurosciences, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

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http://dx.doi.org/10.1007/s00415-019-09214-2DOI Listing
March 2019

Monocyte Function in Parkinson's Disease and the Impact of Autologous Serum on Phagocytosis.

Front Neurol 2018 16;9:870. Epub 2018 Oct 16.

John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.

Increasing evidence implicates involvement of the innate immune system in the initiation and progression of Parkinson's disease (PD). Monocytes and monocyte-derived cells perform a number of functions, such as phagocytosis, chemotaxis, and cytokine secretion, which may be particularly relevant to PD pathology. The behavior of these cells in early-moderate disease, in conditions more similar to the environment has not been fully evaluated. Does monocyte function, including phagocytosis, chemotaxis and cytokine secretion, differ in early-moderate PD compared to age and gender-matched controls? Participants included PD patients ( = 41) with early-moderate stage disease (Hoehn and Yahr ≤2) and age and gender matched controls ( = 41). Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and monocytes were further separated using CD14 magnetic beads. Functional assays, including bead phagocytosis (in standard medium and autologous serum), Boyden chamber trans-well chemotaxis, and cytokine secretion on lipopolysaccharide stimulation were performed. Monocyte surface markers relating to chemotaxis were measured using immunohistochemistry and flow cytometry. Between-group analysis was performed using paired -tests. An autologous serum environment significantly increased bead phagocytosis compared to standard medium as expected, in both patients and controls. When in autologous serum, PD monocytes demonstrated enhanced phagocytosis compared to control monocytes ( = 0.029). The level of serum-based phagocytosis was influenced by complement inactivation and the origin of the serum. There were no significant differences between PD and controls in terms of standard medium based monocyte migration or cytokine secretion in this cohort. Autologous serum has a significant influence on monocyte phagocytosis and reveals increased phagocytic capacity in early-moderate PD compared to controls. These conditions may better reflect the function of monocytes in PD patients than standard medium based phagocytosis assays. Further studies will be required to replicate these results in larger cohorts, including earlier and later stages of disease, and to understand which serum factors are responsible for this observation and the potential mechanistic relevance to PD pathogenesis.
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http://dx.doi.org/10.3389/fneur.2018.00870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198066PMC
October 2018

Imaging intralesional heterogeneity of sodium concentration in multiple sclerosis: Initial evidence from Na-MRI.

J Neurol Sci 2018 04 6;387:111-114. Epub 2018 Feb 6.

Department of Radiology, University of Cambridge, Cambridge, UK; Department of Radiology, Addenbrooke's Hospital, Cambridge, UK.

Sodium MRI (Na-MRI) has been used to non-invasively quantify tissue sodium but has been limited by low spatial resolution. Here we demonstrate for the first time that high resolution Na-MRI reveals the spatial heterogeneity of sodium concentration within a multiple sclerosis (MS) lesion. A patient with treatment-naïve relapsing-remitting MS and a ring-enhancing lesion was imaged using Na-MRI. The periphery of the lesion demonstrated an elevated total sodium content compared to the normal appearing white and grey matter (p<0.01), as well as a heterogeneous distribution of both the total tissue sodium concentration and the intracellular-weighted sodium concentration.
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http://dx.doi.org/10.1016/j.jns.2018.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884312PMC
April 2018

Extracellular Lactate: A Novel Measure of T Cell Proliferation.

J Immunol 2018 02 29;200(3):1220-1226. Epub 2017 Dec 29.

Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0AH, United Kingdom;

Following activation, T cells rapidly divide and acquire effector functions. This energetically demanding process depends upon the ability of T cells to undergo metabolic remodeling from oxidative phosphorylation to aerobic glycolysis, during which glucose is converted into lactate and released extracellularly. In this article, we demonstrate that extracellular lactate can be used to dynamically assess human T cell responses in vitro. Extracellular lactate levels strongly correlated with T cell proliferation, and measuring lactate compared favorably with traditional methods for determining T cell responses (i.e., [H]thymidine incorporation and the use of cell proliferation dyes). Furthermore, we demonstrate the usefulness of measuring lactate as a read-out in conventional suppression assays and high-throughput peptide-screening assays. Extracellular lactate was stably produced over 7 d, and results were reproducibly performed over several freeze-thaw cycles. We conclude that the use of extracellular lactate measurements can be a sensitive, safe, stable, and easy-to-implement research tool for measuring T cell responses and cellular metabolic changes in vitro.
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http://dx.doi.org/10.4049/jimmunol.1700886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776880PMC
February 2018

Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2.

JCI Insight 2017 Aug 17;2(16). Epub 2017 Aug 17.

JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.

The maintenance of peripheral naive T lymphocytes in humans is dependent on their homeostatic division, not continuing emigration from the thymus, which undergoes involution with age. However, postthymic maintenance of naive T cells is still poorly understood. Previously we reported that recent thymic emigrants (RTEs) are contained in CD31+CD25- naive T cells as defined by their levels of signal joint T cell receptor rearrangement excision circles (sjTRECs). Here, by differential gene expression analysis followed by protein expression and functional studies, we define that the naive T cells having divided the least since thymic emigration express complement receptors (CR1 and CR2) known to bind complement C3b- and C3d-decorated microbial products and, following activation, produce IL-8 (CXCL8), a major chemoattractant for neutrophils in bacterial defense. We also observed an IL-8-producing memory T cell subpopulation coexpressing CR1 and CR2 and with a gene expression signature resembling that of RTEs. The functions of CR1 and CR2 on T cells remain to be determined, but we note that CR2 is the receptor for Epstein-Barr virus, which is a cause of T cell lymphomas and a candidate environmental factor in autoimmune disease.
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http://dx.doi.org/10.1172/jci.insight.93739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621870PMC
August 2017

Alemtuzumab use in neuromyelitis optica spectrum disorders: a brief case series.

J Neurol 2016 Jan;263(1):25-9

Alemtuzumab is an anti-CD52 monoclonal antibody recently licensed for use in relapsing-remitting multiple sclerosis. Here, we report our experience of its use in neuromyelitis optica (NMO) spectrum disorders. A retrospective case review of patients treated with alemtuzumab in Cambridge, UK, was conducted to identify those who fulfil the criteria for NMO spectrum disorder. Three cases were identified. Case 1, 9-year-old female, presented with transverse myelitis and bilateral optic neuritis,with one lower medullary and several longitudinally extensive cord lesions. Despite immunosuppression including two courses of alemtuzumab, she continued to relapse, was wheelchair bound and registered blind by age 12, and died at age 18. Case 2, 41-year-old female, presented with bilateral optic neuritis and transverse myelitis with longitudinally extensive cervical cord lesions. Despite three courses of alemtuzumab, she had five relapses with visual impairment and new cord lesions. She later developed tumefactive white matter lesions and died aged 51.Case 3, 31-year-old female, presented with transverse myelitis with longitudinally extensive cervical cord lesions and positive aquaporin-4 antibody. After one course of alemtuzumab, she relapsed with 4 episodes of myelitis with new enhancing lesions and accumulating disability. She became relapse free after rituximab and mycophenolate mofetil. From this case series, we conclude that alemtuzumab failed to prevent disabling relapses and poor outcome in NMO. We hypothesise that rituximab is more effective, as in case 3, because it causes much more prolonged B lymphocyte depletion than alemtuzumab. We therefore caution against the use of alemtuzumab in NMO.
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http://dx.doi.org/10.1007/s00415-015-7925-yDOI Listing
January 2016

Clinical relevance of serum antibodies to extracellular N-methyl-D-aspartate receptor epitopes.

J Neurol Neurosurg Psychiatry 2015 Jul 22;86(7):708-13. Epub 2014 Sep 22.

National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, UK Neurosciences Group, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.

Objective: There are now a large number of requests for N-methyl-D-aspartate receptor autoantibody (NMDAR-Ab) tests, and it is important to assess the clinical relevance of all results, particularly when they are reported as 'Low Positive'.

Methods: The clinical data of 56 patients found Positive or Low Positive by the Oxford live cell-based assay were reviewed. An autoimmune basis for the condition was assigned as 'Definite', 'Possible' or 'Unlikely'. The number of core features (encephalopathy, psychiatric, cognitive, epileptic, extrapyramidal and inflammatory cerebrospinal fluid (CSF)) was tabulated.

Results: Twenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin's lymphoma), 18 (32.1%) a Possible NMDAR-Ab encephalitis and 13 (23.2%) an Unlikely autoimmune syndrome. Serum NMDAR-Ab levels were higher in patients with tumours. Positive NMDAR-Abs were found not only in patients with three or more core features and a Definite syndrome, but also in five patients classified as Possible. Conversely, Low Positive NMDAR-Abs were present in 7 Definite cases as well as in 13 Possible cases. Unlikely patients had mainly Low Positive antibodies and fewer core features. CSF NMDAR-Abs, only available in 11 pairs and at varying time points, broadly related to serum levels and were Positive in 3/3 patients with tumours but in only 2/5 Definite patients, and none of the Possible or Unlikely cases.

Interpretation: Using live cell-based assays, Positive and Low Positive antibodies can be of clinical significance. The number of core clinical features should help to select those patients in whom an immunotherapy intervention might be considered, irrespective of the antibody level.
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http://dx.doi.org/10.1136/jnnp-2014-308736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055984PMC
July 2015

Mode of action and clinical studies with alemtuzumab.

Exp Neurol 2014 Dec 2;262 Pt A:37-43. Epub 2014 May 2.

Dept. of Clinical Neurosciences, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK. Electronic address:

The lymphocyte depleting anti-CD52 monoclonal antibody alemtuzumab has been used in Cambridge, UK, as an experimental treatment of multiple sclerosis since 1991. One phase-2 trial (CAMMS-223) and two phase-3 studies (CARE-MS1 and CARE-MS2) have confirmed its efficacy in treatment-naive patients, and have established superiority over interferon beta-1a in patients who continue to relapse in spite of first-line therapy (Cohen et al., 2012; Coles et al., 2008; Coles et al., 2012a; Coles et al., 2012b). Despite causing a prolonged T cell lymphopenia, significant infections have not been an issue following treatment; rather alemtuzumab's primary safety concern is secondary autoimmunity, occurring up to five years after treatment and maximally at two years: 30% of patients develops thyroid autoimmunity, and 1% develops idiopathic thrombocytopenic purpura (ITP). In addition, 4 out of 1486 patients (<0.3%) treated on the commercially sponsored studies developed glomerulonephritis. Two of these patients developed anti-glomerular basement membrane disease, a condition which may result in renal failure unless treated aggressively. In September 2013, the European Medicine Agency (EMA) ruled that the benefit-to-risk balance for alemtuzumab was favourable, approving it as a first-line therapy for adults with active relapsing remitting multiple sclerosis (under the trade name Lemtrada). Lemtrada is now also approved as a treatment of multiple sclerosis in Canada, Australia, Switzerland, Israel, Mexico and Brazil. However, in December 2013, Lemtrada failed to gain approval from the U.S. Food and Drug Administration (FDA), with concerns over trial design and safety stated as the main reasons. In this review we describe our local experience and explain the rationale behind its initial use as a treatment of multiple sclerosis and behind the design of the commercially sponsored trials, summarising their key findings. We also sum up our understanding of its mechanism of action.
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http://dx.doi.org/10.1016/j.expneurol.2014.04.018DOI Listing
December 2014

Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis.

J Neurol Neurosurg Psychiatry 2014 Jul 24;85(7):795-8. Epub 2013 Dec 24.

Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

Objective: We have previously shown that autoimmunity following alemtuzumab treatment of multiple sclerosis can be predicted by high baseline serum interleukin IL-21 (IL-21), as measured using a now 'redundant' enzyme linked immunosorbent assay (ELISA). Here we ask whether currently available ELISAs have similar prognostic value.

Design: Serum IL-21 from 141 individuals with relapsing remitting multiple sclerosis was measured using the now 'redundant' IL-21 ELISA and five further currently available kits. All patients had been treated with alemtuzumab; 61/141 had developed secondary autoimmunity.

Results: The 'redundant kit', and one current kit, confirmed higher baseline serum IL-21 in patients with autoimmunity (542 pg/mL vs. 222 pg/mL and 53.1 pg/mL vs. 9.3 pg/mL respectively) and showed positive correlation. However, only the 'redundant' kit had predictive utility.

Conclusions: Currently available IL-21 ELISA kits should not be used to counsel individuals with multiple sclerosis considering treatment with alemtuzumab.
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http://dx.doi.org/10.1136/jnnp-2013-307042DOI Listing
July 2014

Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation.

Proc Natl Acad Sci U S A 2013 Dec 26;110(50):20200-5. Epub 2013 Nov 26.

Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.

The association between lymphopenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28(-)CD57(+)), highly proliferative (Ki67(+)), oligoclonal, memory-like CD4 and CD8 T cells (CCR7(-)CD45RA(-) or CCR7(-)CD45RA(+)) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopenia-associated autoimmunity in humans.
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http://dx.doi.org/10.1073/pnas.1313654110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864306PMC
December 2013

Immune competence after alemtuzumab treatment of multiple sclerosis.

Neurology 2013 Sep 7;81(10):872-6. Epub 2013 Aug 7.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Objective: To determine the immunocompetency of patients with multiple sclerosis treated with the lymphodepleting humanized monoclonal antibody alemtuzumab.

Methods: In this pilot case-control study, we assessed immunocompetence in 24 patients after alemtuzumab treatment by measuring antibody responses to 3 vaccines (diphtheria, tetanus, and poliomyelitis vaccine, Haemophilus influenzae type b and meningococcal group C conjugate vaccine, and pneumococcal polysaccharide vaccine). In 20 patients, antibodies to common viruses (mumps, rubella, varicella-zoster, and Epstein-Barr virus) were measured before alemtuzumab treatment, then at 1 and 9-11 months after treatment. Results were compared with well-defined historical controls.

Results: Serum antibodies against common viruses remained detectable after treatment, and vaccine responses were normal to T-cell-dependent recall antigens (tetanus, diphtheria, and polio), a T-cell-dependent novel antigen (meningococcus C), and T-cell-independent antigens (pneumococcal). There was no evidence for a diminished response to vaccinations in 5 patients studied within 6 months of alemtuzumab treatment.

Conclusion: In this small historically controlled pilot study, we demonstrated i) retained humoral immunologic memory (in the form of antibodies against common viruses and response to recall antigens), and ii) the retained ability to mount a humoral immune response against a novel antigen after treatment with alemtuzumab.

Classification Of Evidence: This pilot study provides Class III evidence that patients with relapsing-remitting multiple sclerosis appear immunocompetent after treatment with alemtuzumab.
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http://dx.doi.org/10.1212/WNL.0b013e3182a35215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885219PMC
September 2013

Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis.

Brain 2013 Sep 17;136(Pt 9):2888-903. Epub 2013 Jul 17.

Division of Brain Sciences, Department of Medicine, Imperial College, London, UK.

Autologous haematopoietic stem cell transplantation has been tried as one experimental strategy for the treatment of patients with aggressive multiple sclerosis refractory to other immunotherapies. The procedure is aimed at ablating and repopulating the immune repertoire by sequentially mobilizing and harvesting haematopoietic stem cells, administering an immunosuppressive conditioning regimen, and re-infusing the autologous haematopoietic cell product. 'Non-myeloablative' conditioning regimens to achieve lymphocytic ablation without marrow suppression have been proposed to improve safety and tolerability. One trial with non-myeloablative autologous haematopoietic stem cell transplantation reported clinical improvement and inflammatory stabilization in treated patients with highly active multiple sclerosis. The aim of the present study was to understand the changes in the reconstituted immune repertoire bearing potential relevance to its mode of action. Peripheral blood was obtained from 12 patients with multiple sclerosis participating in the aforementioned trial and longitudinally followed for 2 years. We examined the phenotype and function of peripheral blood lymphocytes by cell surface or intracellular staining and multi-colour fluorescence activated cell sorting alone or in combination with proliferation assays. During immune reconstitution post-transplantation we observed significant though transient increases in the proportion of CD4+ FoxP3+ T cells and CD56(high) natural killer cell subsets, which are cell subsets associated with immunoregulatory function. CD8+ CD57+ cytotoxic T cells were persistently increased after therapy and were able to suppress CD4+ T cell proliferation with variable potency. In contrast, a CD161(high) proinflammatory CD8+ T cell subset was depleted at all time-points post-transplantation. Phenotypic characterization revealed that the CD161(high)CD8+ T cells were mucosal-associated invariant T cells, a novel cell population originating in the gut mucosa but expressing the central nervous system-homing receptor CCR6. Detection of mucosal-associated invariant T cells in post-mortem multiple sclerosis brain white matter active lesions confirmed their involvement in the disease pathology. Intracellular cytokine staining demonstrated interferon γ and interleukin 17 production and lack of interleukin 10 production, a pro-inflammatory profile. Mucosal-associated invariant T cell frequency did not change in patients treated with interferon β; and was more depleted after autologous haematopoietic stem cell transplantation than in patients who had received high-dose cyclophosphamide (n = 7) or alemtuzumab (n = 21) treatment alone, suggesting an additive or synergistic effect of the conditioning regime components. We propose that a favourably modified balance of regulatory and pro-inflammatory lymphocytes underlies the suppression of central nervous system inflammation in patients with multiple sclerosis following non-myeloablative autologous haematopoietic stem cell transplantation with a conditioning regimen consisting of cyclophosphamide and alemtuzumab.
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http://dx.doi.org/10.1093/brain/awt182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754461PMC
September 2013

Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis.

J Neurol Neurosurg Psychiatry 2012 Mar 5;83(3):298-304. Epub 2011 Nov 5.

Department of Neurology, University of Cambridge, Cambridge, UK.

Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined.

Methods: The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis.

Results: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10(9) cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10(9)/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10(9) cells/l) and CD4 lymphocytes (LLN ≥0.4×10(9) cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up.

Conclusions: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.
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http://dx.doi.org/10.1136/jnnp-2011-300826DOI Listing
March 2012

Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity.

Brain 2010 Aug 21;133(Pt 8):2232-47. Epub 2010 Jul 21.

Department of Clinical Neuroscience, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.

Treatment of early relapsing-remitting multiple sclerosis with the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath [registered trade mark]) significantly reduced the risk of relapse and accumulation of disability compared with interferon β-1a in a phase 2 trial [Coles et al., (Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786-801)]. Patients treated with alemtuzumab experienced an improvement in disability at 6 months that was sustained for at least 3 years. In contrast, those treated with interferon β-1a steadily accumulated disability. Here, by post hoc subgroup analyses of the CAMMS223 trial, we show that among participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity on-trial, disability improved after alemtuzumab but not following interferon β-1a. This suggests that disability improvement after alemtuzumab is not solely attributable to its anti-inflammatory effect. So we hypothesized that lymphocytes, reconstituting after alemtuzumab, permit or promote brain repair. Here we show that after alemtuzumab, and only when specifically stimulated with myelin basic protein, peripheral blood mononuclear cell cultures produced increased concentrations of brain-derived neurotrophic factor, platelet-derived growth factor and ciliary neurotrophic factor. Analysis by reverse transcriptase polymerase chain reaction of cell separations showed that the increased production of ciliary neurotrophic factor and brain-derived neurotrophic factor after alemtuzumab is attributable to increased production by T cells. Media from these post-alemtuzumab peripheral blood mononuclear cell cultures promoted survival of rat neurones and increased axonal length in vitro, effects that were partially reversed by neutralizing antibodies against brain-derived nerve growth factor and ciliary neurotrophic factor. This conditioned media also enhanced oligodendrocyte precursor cell survival, maturation and myelination. Taken together, the clinical analyses and laboratory findings support the interpretation that improvement in disability after alemtuzumab may result, in part, from neuroprotection associated with increased lymphocytic delivery of neurotrophins to the central nervous system.
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http://dx.doi.org/10.1093/brain/awq176DOI Listing
August 2010

New treatment strategies in multiple sclerosis.

Exp Neurol 2010 Sep 12;225(1):34-9. Epub 2010 Jun 12.

Dept. of Clinical Neurosciences, Box 165 Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.

Multiple sclerosis is the most common, non-traumatic, disabling neurological disease of young adults, affecting an estimated two million people worldwide. At onset multiple sclerosis can be categorised clinically into relapsing remitting MS (RRMS - 85-90% of patients) or primary progressive MS (PPMS). Relapses typically present sub-acutely over hours to days with neurological symptoms persisting for days to weeks before they gradually dissipate. At first full recovery is the norm, later patients accumulate deficits and ultimately most convert to a secondary progressive phase (SPMS), characterised by deficits that increase in the absence of further relapses. The clinical picture reflects the complex interplay of focal inflammation, demyelination and axonal degeneration occurring within the central nervous system. Since the introduction of a genuine disease-modifying drug, interferon-beta1b in 1993, there has been a growing interest from academia and pharmaceutical companies alike in multiple sclerosis therapy. In part this effort has focused on investigating the "window of therapeutic opportunity" within the natural history of the disease: it is becoming increasingly clear that immunotherapies are not useful in the secondary phase of the disease but may offer long-term benefit if given early in the relapsing-remitting phase. In part, attention is being paid to the details of dosing and administration of the various licensed therapies, but there is also a significant research effort to explore new ways to treat the disease. In this review, we first sketch the landscape of novel therapies in multiple sclerosis and then discuss in detail approaches which are likely to emerge over the next few years.
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http://dx.doi.org/10.1016/j.expneurol.2010.06.003DOI Listing
September 2010

A novel strategy to reduce the immunogenicity of biological therapies.

J Immunol 2010 Jul 2;185(1):763-8. Epub 2010 Jun 2.

Department of Medicine, University of Auckland, Auckland, New Zealand.

Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing-remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p < 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. Long-lasting "high-zone" tolerance to a biological therapy may be induced by pretreatment with a high i.v. dose of a drug variant, altered to reduce target-binding.
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http://dx.doi.org/10.4049/jimmunol.1000422DOI Listing
July 2010

B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis.

J Clin Immunol 2010 Jan 10;30(1):99-105. Epub 2009 Sep 10.

Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Introduction: Treatment with alemtuzumab is highly effective in relapsing-remitting multiple sclerosis; however, 30% of patients develop autoimmunity. Alemtuzumab (previously called Campath 1-H) induces a prolonged T-cell lymphopenia with memory cells dominating the reconstituting T-cell pool for at least 3 months.

Results: Here we show that B-cell recovery is rapid, returning to baseline by 3 months and rising to 165% of baseline by 12 months after treatment. Immature transitional 1 B cells are the predominant cell type 1 month after treatment. This coincides with a surge in serum B-cell activating factor (BAFF), which remains elevated by 33% for at least 12 months after alemtuzumab. BAFF is critical for transition to the mature naive B-cell phenotype, which dominates from 3 months after alemtuzumab. Differentiation to memory B cells is slow so there are radical and prolonged alterations to the B-cell pool after alemtuzumab.
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http://dx.doi.org/10.1007/s10875-009-9327-3DOI Listing
January 2010

IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H).

J Clin Invest 2009 Jul 22;119(7):2052-61. Epub 2009 Jun 22.

Department of Clinical Neuroscience, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.

Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity.
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http://dx.doi.org/10.1172/JCI37878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701868PMC
July 2009

Campath-1H treatment of multiple sclerosis.

Neurodegener Dis 2008 ;5(1):27-31

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Campath-1H is a humanised monoclonal antibody that targets CD52, a cell surface protein expressed on lymphocytes, monocytes and eosinophils. A single dose of Campath-1H leads to a rapid and profound lymphopenia. Campath-1H has been used in Cambridge as an experimental treatment of multiple sclerosis for more than 15 years. Here, we summarise our clinical and laboratory findings, describing how this prototypical 'bench to bedside' therapy continues to inform basic science, revealing aspects of the pathogenesis of multiple sclerosis and autoimmunity.
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http://dx.doi.org/10.1159/000109935DOI Listing
March 2008

Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis.

Eur J Immunol 2005 Nov;35(11):3332-42

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Following lymphocyte depletion, homeostatic mechanisms drive the reconstitution of lymphocytes. We prospectively studied this process in 16 patients for 1 year after a single pulse of treatment with Campath-1H, a humanised anti-CD52 monoclonal antibody. We observed two phases of lymphocyte reconstitution. In the first 6 months after treatment the precursor frequency and proliferation index of the patients' autologous mixed lymphocyte reaction increased; the depleted T cell pool was dominated by memory T cells, especially (CD4+)CD25high T cells, a putative regulatory phenotype; and there was a non-significant rise in peripheral mononuclear cell FoxP3 mRNA expression and fall in constitutive cytokine mRNA expression. In the later phase, from 6-to-12 months after Campath-1H, these changes reversed and there was a rise in ROG mRNA expression. However, total CD4+ numbers remained below 50% of pre-treatment levels at 12 months, perhaps reflecting a failure in homeostasis. This was not due to an impaired IL-7 response, as in rheumatoid arthritis, nor to a lack of IL-7 receptors, which are found on fewer human (CD4+)CD25high than naive cells. We speculate that CCL21 and IL-15 responses to lymphopaenia may be suboptimal in multiple sclerosis.
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http://dx.doi.org/10.1002/eji.200535075DOI Listing
November 2005

Emission factors and importance of PCDD/Fs, PCBs, PCNs, PAHs and PM10 from the domestic burning of coal and wood in the U.K.

Environ Sci Technol 2005 Mar;39(6):1436-47

Department of Environmental Science, IENS, Lancaster University, Lancaster LA1 4YQ, UK.

This paper presents emission factors (EFs) derived for a range of persistent organic pollutants (POPs) when coal and wood were subject to controlled burning experiments, designed to simulate domestic burning for space heating. A wide range of POPs were emitted, with emissions from coal being higher than those from wood. Highest EFs were obtained for particulate matter, PM10, (approximately 10 g/kg fuel) and polycyclic aromatic hydrocarbons (approximately 100 mg/ kg fuel for sigmaPAHs). For chlorinated compounds, EFs were highest for polychlorinated biphenyls (PCBs), with polychlorinated naphthalenes (PCNs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) being less abundant. EFs were on the order of 1000 ng/kg fuel for sigmaPCBs, 100s ng/ kg fuel for sigmaPCNs and 100 ng/kg fuel for sigmaPCDD/Fs. The study confirmed that mono- to trichlorinated dibenzofurans, Cl1,2,3DFs, were strong indicators of low temperature combustion processes, such as the domestic burning of coal and wood. It is concluded that numerous PCB and PCN congeners are routinely formed during the combustion of solid fuels. However, their combined emissions from the domestic burning of coal and wood would contribute only a few percent to annual U.K. emission estimates. Emissions of PAHs and PM10 were major contributors to U.K. national emission inventories. Major emissions were found from the domestic burning for Cl1,2,3DFs, while the contribution of PCDD/F-sigmaTEQ to total U.K. emissions was minor.
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http://dx.doi.org/10.1021/es048745iDOI Listing
March 2005

Polychlorinated dibenzo-p-dioxin and furan (PCDD/F) uptake by pasture.

Environ Sci Technol 2002 Jun;36(11):2372-8

Department of Environmental Science, Institute of Environmental and Natural Sciences, Lancaster University, UK.

Uptake of airborne PCDD/Fs by a native pasture sward was studied. The concentrations of the less chlorinated PCDD/Fs (up to and including the Cl5DD/Fs) in pasture harvested on the same day after 2, 6, and 12 weeks exposure were the same, implying that air-pasture steady-state was reached within 2 weeks of exposure. The implications of these observations for the relative importance of input (atmospheric deposition, soil resuspension) and loss (photolysis, degradation, volatilization, cuticular shedding, and growth dilution) processes are discussed and inferences made about the controlling factors. The concentrations of the more chlorinated PCDD/Fs were more variable. We infer that they were influenced by wash-off of particle- and surface-bound chemical. Up to 4% of the Cl2-4DD/F and 4-13% of the Cl5-8DD/F loading on the pasture was estimated to have been supplied by adhering soil particles, with the remainder supplied by atmospheric deposition. Between 0.04 and 0.66 kg of each homologue group (excluding Cl2DFs) is estimated to be transferred annually from the atmosphere to pasture in the U.K.
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http://dx.doi.org/10.1021/es010176gDOI Listing
June 2002