One of the few bright spots to emerge from the history of relations between American Indians and the federal government is the remarkable record of the Indian Health Service (IHS). The IHS has raised the health status of Indians to approximate that of most other Americans, a striking achievement in the light of the poverty and stark living conditions experienced by this population. The gains occurred in spite of chronically low funding and can be attributed to the combination of vision, stubbornness, and political savvy of the agency's physician directors and the support of a handful of tribal leaders and powerful allies in the Congress and the White House. Despite the agency's imperfections and the sizeable health problems that still exist among American Indians and Alaskan Natives, the IHS is an example of one federal program that has worked.
A barrier to the successful development of new disease treatments is the timely recruitment of participants to experimental medicine studies that are primarily designed to investigate biological mechanisms rather than evaluate clinical efficacy. The aim of this study was to analyse the performance of three recruitment sources and the effect of publicity events during the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D). ; This work is funded by the JDRF (9-2011-253), the Wellcome Trust (091157) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 241447 (NAIMIT). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). ; This is the final version of the article. It first appeared from BMC via http://dx.doi.org/10.1186/s13063-015-0583-7
Seasonal variations are rarely considered a contributing component to human tissue function or health, although many diseases and physiological process display annual periodicities. Here we find more than 4,000 protein-coding mRNAs in white blood cells and adipose tissue to have seasonal expression profiles, with inverted patterns observed between Europe and Oceania. We also find the cellular composition of blood to vary by season, and these changes, which differ between the United Kingdom and The Gambia, could explain the gene expression periodicity. With regards to tissue function, the immune system has a profound pro-inflammatory transcriptomic profile during European winter, with increased levels of soluble IL-6 receptor and C-reactive protein, risk biomarkers for cardiovascular, psychiatric and autoimmune diseases that have peak incidences in winter. Circannual rhythms thus require further exploration as contributors to various aspects of human physiology and disease. ; The Gambian study providing data for analysis was supported by core funding MC-A760-5QX00 to the International Nutrition Group by the UK Medical Research Council (MRC) and the UK Department for the International Development (DFID) under the MRC/DFID Concordat agreement. This work was supported by the JDRF UK Centre for Diabetes-Genes, Autoimmunity and Prevention (D-GAP; 4-2007-1003), the JDRF (9-2011-253), the Wellcome Trust (WT061858/091157), the National Institute for Health Research Cambridge Biomedical Research Centre (CBRC) and the Medical Research Council (MRC) Cusrow Wadia Fund. The research leading to these results has received funding from the European Union's 7th Framework Programme (FP7/2007–2013) under grant agreement no.241447 (NAIMIT). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (WT100140). X.C.D. was a University of Cambridge/Wellcome Trust Infection and Immunity PhD student. R.C.F. is funded by a JDRF post-doctoral fellowship (3-2011-374). C.W. and H.G are funded by ...
The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the β-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the β-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the β-cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors. We find that T1D-associated loci are enriched with newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human β cells. Our study illustrates how β cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D. ; L.Pasquali was supported by grants from the Spanish Ministry of Economy and Competitiveness (nos. BFU2014-58150-R and SAF2017-86242-R), Marató TV3 (no. 201624.10) and a young investigator award from the Spanish Society of Diabetes (Ayuda SED a Proyectos de Investigación, no. 2017-SED). L.Pasquali is a recipient of a Ramon y Cajal contract from the Spanish Ministry of Economy and Competitiveness (no. RYC-2013-12864). The Pasquali lab is further supported by Instituto de Salud Carlos III (no. PIE16/00011). M.R. is supported by an FI Agència de Gestió d'Ajuts Universitaris i de Recerca PhD fellowship (no. 2019FI_B100203). J.J. was supported by a Marie Skłodowska-Curie Actions fellowship grant from the Horizons 2020 European Union (EU) Programme (project no. 660449). M.I.A. was supported by a FRIA fellowship from the Fonds de la Recherche Scientifique (FNRS) (no. 26410496). Human islets were provided through the European Consortium for Islet Transplantation distribution program for basic research supported by JDRF (no. 31-2008-416). D.L.E. was supported by the Walloon Region through the FRFS-WELBIO Fund for Strategic Fundamental research (no. CR-2015A-06s and CR-2019C-04) and by grants from the Fonds National de la Recherche Scientifique (no. T003613F), the Horizon 2020 Programme (project T2Dsystems, no. GA667191), Brussels Capital Region Innoviris (project DiaType, no. 2017-PFS-24), Dutch Diabetes Research Fundation (project Innovate2CureType1, DDRF; no. 2018.10.002) and the Innovative Medicines Initiative 2 Joint Undertaking (project INNODIA, no. 115797). This Innovative Medicines Initiative 2 Joint Undertaking receives support from the EU's Horizon 2020 Research and Innovation Programme and European Federation of Pharmaceutical Industries and Associations, JDRF and the Leona M. and Harry B. Helmsley Charitable Trust (project INNODIA, no. 115797). T.O.M. and D.L.E. were supported by a grant from the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases-Human Islet Research Network Consortium (no. 1UC4DK104166-01). Part of the work was performed at the Environmental Molecular Sciences Laboratory, a US Department of Energy national scientific user facility located at Pacific Northwest National Laboratory. Battelle operates the Pacific Northwest National Laboratory for the Department of Energy (contract no. DE-AC05-76RLO01830).
Long-range interactions between regulatory elements and gene promoters play key roles in transcriptional regulation. The vast majority of interactions are uncharted, constituting a major missing link in understanding genome control. Here, we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary hematopoietic cell types. We show that promoter interactions are highly cell type specific and enriched for links between active promoters and epigenetically marked enhancers. Promoter interactomes reflect lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched in genetic variants linked with altered expression of genes they contact, highlighting their functional role. We exploit this rich resource to connect non-coding disease variants to putative target promoters, prioritizing thousands of disease-candidate genes and implicating disease pathways. Our results demonstrate the power of primary cell promoter interactomes to reveal insights into genomic regulatory mechanisms underlying common diseases. ; This work was supported by the following grants: UK Medical Research Council (MR/L007150/1, MC_UP_1302/1, MC_UP_1302/3, MC_UP_1302/5), UK Biotechnology and Biological Sciences Research Council (BB/J004480/1), ERC (DEVOCHROMO advanced grant), JDRF (9-2011-253, 5-SRA-2015-130), Wellcome Trust (089989, 091157, 095908, 100140, 107212, 107881), European Union 7th Framework Programme (FP7/2007-2013, grant agreements 241447 [NAIMIT] and 282510 [BLUEPRINT]), NHS Blood and Transplant, NIHR (PG-0310-1002), and BHF (RG/09/12/28096). K.D. is funded by NHS Health Education England. M.F. is supported by the BHF Cambridge Centre of Excellence (RE/13/6/30180). S.P.W., M.K., D.R.Z., and O.S. are funded by the European Molecular Biology Laboratory. ; This is the final version of the article. It first appeared from Elsevier (Cell Press) via https://doi.org/10.1016/j.cell.2016.09.037
BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735. ; JDRF (Grant ID: 9-2011-253), Wellcome Trust (Grant IDs: 091157, 089989, 097997/Z/11/Z), National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, European Union's 7th Framework Programme (FP7/2007-2013) (Grant ID: 241447 (NAIMIT)), Sir Jules Thorn Charitable Trust (Grant ID: 13/JTA), Medical Research Council (Grant ID: G0800860), The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (Grant ID: 100140) ; This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pmed.1002139
