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2.  Islet transplantation from a nationally funded UK centre reaches socially deprived groups and improves metabolic outcomes 
Diabetologia  2015;58(6):1300-1308.
Type 1 diabetes complicated by hypoglycaemia is prevalent in socioeconomically deprived populations. Islet transplantation is of proven efficacy in type 1 diabetes complicated by hypoglycaemia, but it is not known if nationally funded programmes reach the socioeconomically deprived. Our aim was to determine: (1) socioeconomic indices in participants referred to our nationally funded programme; and (2) if metabolic outcomes in our transplant recipients were improved.
Participants referred (n = 106) and receiving transplants (n = 18; 32 infusions) were examined with respect to socioeconomic status (deprivation category score) and their ability to work and drive. In participants followed for ≥12 months after transplantation, metabolic and anthropometric measurements (n = 14) were recorded pre- and post-transplant (assessed ~1, ~3, ~6 and ~12 months with mixed-meal tolerance tests and 6 day continuous glucose monitoring assessments). Donor data was also examined.
There was a greater prevalence of socioeconomic deprivation in referred and transplant recipients than the general population (p < 0.05). Of the transplant recipients, 73% were socioeconomically deprived, 88% did not hold a driver’s license and 94% had reduced ability to work (all p < 0.01 vs referred participants). Donors were predominantly obese and included circulatory death donors. At 12 months, 93% of participants who had received transplants had graft function, diminished frequency of hypoglycaemia (10 [4–11] vs 0 [0–2] hypoglycaemic episodes/week), improved awareness of hypoglycaemia (Gold score 7 [5–7] vs 1 [1–2]) and glycaemic control (HbA1c: 7.9% [7.2–8.5%]; 63 [55–69] mmol/mol vs 7.2% [6.8–7.5%]; 55 [51–58] mmol/mol), diminished glycaemic lability and decreased central adiposity (all p < 0.05).
A nationally funded islet transplant programme reaches the socioeconomically deprived and outcomes are significantly improved in this group.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-015-3554-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC4415991  PMID: 25810037
Hypoglycaemia; Impaired awareness of hypoglycaemia; Islet transplantation; Socioeconomic deprivation
3.  Increased Cycling Cell Numbers and Stem Cell Associated Proteins as Potential Biomarkers for High Grade Human Papillomavirus+ve Pre-Neoplastic Cervical Disease 
PLoS ONE  2014;9(12):e115379.
High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish those who may progress to cancer from those who may be treated more conservatively.
PMCID: PMC4274002  PMID: 25531390
4.  CpG-containing immunostimulatory DNA sequences elicit TNF-α–dependent toxicity in rodents but not in humans 
The Journal of Clinical Investigation  2009;119(9):2564-2576.
CpG-containing immunostimulatory DNA sequences (ISS), which signal through TLR9, are being developed as a therapy for allergic indications and have proven to be safe and well tolerated in humans when administrated via the pulmonary route. In contrast, ISS inhalation has unexplained toxicity in rodents, which express TLR9 in monocyte/macrophage lineage cells as well as in plasmacytoid DCs (pDCs) and B cells, the principal TLR9-expressing cells in humans. We therefore investigated the mechanisms underlying this rodent-specific toxicity and its implications for humans. Mice responded to intranasally administered 1018 ISS, a representative B class ISS, with strictly TLR9-dependent toxicity, including lung inflammation and weight loss, that was fully reversible and pDC and B cell independent. Knockout mouse experiments demonstrated that ISS-induced toxicity was critically dependent on TNF-α, with IFN-α required for TNF-α induction. In contrast, human PBMCs, human alveolar macrophages, and airway-derived cells from Ascaris suum–allergic cynomolgus monkeys did not produce appreciable TNF-α in vitro in response to ISS stimulation. Moreover, sputum of allergic humans exposed to inhaled ISS demonstrated induction of IFN-inducible genes but minimal TNF-α induction. These data demonstrate that ISS induce rodent-specific TNF-α–dependent toxicity that is absent in humans and reflective of differential TLR9 expression patterns in rodents versus humans.
PMCID: PMC2735936  PMID: 19726873
5.  Isolation and characterization of human interleukin-10–secreting T cells from peripheral blood 
Human immunology  2010;71(3):225-234.
Recent studies have expanded our understanding of the role of the anti-inflammatory cytokine interleukin (IL)–10, produced by multiple lineages of both human and murine T cells, in regulating the immune response. Here, we demonstrate that the small percentage of circulating CD4+ T cells that secrete IL-10 can be isolated from human peripheral blood and, importantly, we have optimized a protocol to expand these cells in both antigen-specific and polyclonal manners. Expanded CD4+IL-10+ T cells abrogate proliferation and T helper (Th) 1–like cytokine production in an antigen-specific manner, and to a lesser extent exhibit bystander suppressive capacity. CD4+IL-10+ T cells are suppressive in a cell contact–dependent way, though they do not require secretion of IL-10 for their suppressive role in vitro. CD4+IL-10+ T cells have an activated phenotype, with high expression of CD25, CD69, and cytotoxic T-lymphocyte antigen-4, and are largely FoxP3 negative. This novel method for the isolation and expansion of suppressive IL-10–secreting T cells has important implications both for further research and clinical therapeutic development.
PMCID: PMC3399767  PMID: 20034527
Interleukin-10; Induced regulatory T cells
7.  Peptide immunotherapy in allergic asthma generates IL-10–dependent immunological tolerance associated with linked epitope suppression 
The Journal of Experimental Medicine  2009;206(7):1535-1547.
Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other (“linked”) epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10+ T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti–IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans.
PMCID: PMC2715096  PMID: 19528258

Results 1-7 (7)