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.
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.
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.
ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Neutralizing monoclonal antibody (NmAb) treatments have received Emergency Use Authorization to treat patients with mild or moderate COVID-19 infection. To date, no real- world ...data on the efficacy of NmAbs have been reported from clinical practice. We assessed the impact of NmAb treatment given in the outpatient clinical practice setting on hospital utilization.
Methods
Electronic medical records were used to identify adult COVID-19 patients who received NmAbs (bamlanivimab BAM or casirivimab and imdevimab REGN-COV2) and historic COVID-19 controls. Post-index hospitalization rates were compared.
Results
707 confirmed COVID-19 patients received NmAbs and 1709 historic COVID-19 controls were included; 553 (78%) received BAM, 154 (22%) received REGN-COV2. Patients receiving NmAb infusion had significantly lower hospitalization rates (5.8% vs 11.4%, P < .0001), shorter length of stay if hospitalized (mean, 5.2 vs 7.4 days; P = .02), and fewer ED visits within 30 days post-index (8.1% vs 12.3%, P = .003) than controls. Hospitalization-free survival was significantly longer in NmAb patients compared with controls (P < .0001). There was a trend towards a lower hospitalization rate among patients who received NmAbs within 2–4 days after symptom onset. In multivariate analysis, having received an NmAb transfusion was independently associated with a lower risk of hospitalization after adjustment for age, sex, race, BMI, and referral source (adjusted HR 95% CI, .54 0.38–0.79; P = .0012). Overall mortality was not different between the 2 groups.
Conclusions
NmAb treatment reduced hospital utilization, especially when received within a few days of symptom onset. Further study is needed to validate these findings.
In a real-life clinical setting, we found that receipt of neutralizing monoclonal antibody (NmAb) treatment significantly reduced hospital utilization among patients with COVID-19 with mild to moderate disease, especially if NmAb treatment was received ≤4 days after symptom onset.
Prior evidence indicates that predictors of weight loss outcomes after gastric bypass surgery fall within 5 domains: 1) presurgical factors, 2) postsurgical psychosocial variables (e.g., support ...group attendance), 3) postsurgical eating patterns, 4) postsurgical physical activity, and 5) follow-up at postsurgical clinic. However, little data exist on which specific behavioral predictors are most associated with successful outcomes (e.g.,≥ 50% excess weight loss) when considering the 5 domains simultaneously. The objective of this study was to specify the behavioral variables, and their respective cutoff points, most associated with successful weight loss outcomes.
Signal detection analysis evaluated associations between 84 pre- and postsurgical behavioral variables (within the 5 domains) and successful weight loss at ≥ 1 year in 274 postgastric bypass surgery patients.
Successful weight loss was highest (92.6%) among those reporting dietary adherence of>3 on a 9-point scale (median = 5) who grazed no more than once-per-day. Among participants reporting dietary adherence<3 and grazing daily or less, success rates more than doubled when highest lifetime body mass index was<53.7 kg/m(2). Success rates also doubled for participants with dietary adherence = 3 if attending support groups. No variables from the physical activity or postsurgical follow-up domains were significant, nor were years since surgery. The overall model's sensitivity = .62, specificity = .92.
To our knowledge, this is the first study to simultaneously consider the relative contribution of behavioral variables within 5 domains and offer clinicians an assessment algorithm identifying cut-off points for behaviors most associated with successful postsurgical weight loss. Such data may inform prospective study designs and postsurgical interventions.
Summary Background Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations ...include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. Methods We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z -score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Findings Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10−109 for rs2282679, in GC ); 11q12 (p=2·1×10−27 for rs12785878, near DHCR7 ); and 11p15 (p=3·3×10−20 for rs10741657, near CYP2R1 ). Variants at an additional locus (20q13, CYP24A1 ) were genome-wide significant in the pooled sample (p=6·0×10−10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95% CI 2·20–2·78, p=2·3×10−48 ) or lower than 50 nmol/L (1·92, 1·70–2·16, p=1·0×10−26 ) compared with those in the lowest quartile. Interpretation Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. Funding Full funding sources listed at end of paper (see Acknowledgments).
Type 1 diabetes and celiac disease, both of which are associated with HLA class II genes, cosegregate in populations, suggesting a common genetic origin. In this article, the authors tested whether ...any non-HLA loci are shared. They report susceptibility alleles shared by both diseases, indicating that common biologic mechanisms underlie these immune-mediated disorders.
Type 1 diabetes and celiac disease cosegregate in populations, suggesting a common genetic origin. These authors report susceptibility alleles shared by both diseases, indicating that common biologic mechanisms underlie these immune-mediated disorders.
Type 1 diabetes is caused by autoimmune destruction of the insulin-producing beta cells in the pancreatic islets. The disease affects approximately 0.4% of persons of European origin and is strongly clustered in families. The major susceptibility genes — the HLA class II loci, HLA-DQB1 and HLA-DRB1 on chromosome 6p21 — act in combination with many other non-HLA loci across the genome,
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with unknown environmental factors playing a major role.
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Celiac disease, which results from an immune, inflammatory reaction in the small intestine to proteins in ingested barley, wheat, and rye gluten, occurs in approximately 0.1% of persons of . . .
The main problems in drawing causal inferences from epidemiological case-control studies are confounding by unmeasured extraneous factors, selection bias and differential misclassification of ...exposure. In genetics the first of these, in the form of population structure, has dominated recent debate. Population structure explained part of the significant +11.2% inflation of test statistics we observed in an analysis of 6,322 nonsynonymous SNPs in 816 cases of type 1 diabetes and 877 population-based controls from Great Britain. The remainder of the inflation resulted from differential bias in genotype scoring between case and control DNA samples, which originated from two laboratories, causing false-positive associations. To avoid excluding SNPs and losing valuable information, we extended the genomic control method by applying a variable downweighting to each SNP.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region. The aim of this ...study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10)): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
FUT2 encodes the α(1,2) fucosyltransferase that determines blood group secretor status. Homozygotes (A/A) for the common nonsense mutation rs601338A>G (W143X) are nonsecretors and are unable to ...express histo-blood group antigens in secretions and on mucosal surfaces. This mutation has been reported to provide resistance to Norovirus and susceptibility to Crohn's disease, and hence we aimed to determine if it also affects risk of type 1 diabetes.
rs601338A>G was genotyped in 8,344 patients with type 1 diabetes, 10,008 control subjects, and 3,360 type 1 diabetic families. Logistic regression models were used to analyze the case-control collection, and conditional logistic regression was used to analyze the family collection. RESULTS The nonsecretor A/A genotype of rs601338A>G was found to confer susceptibility to type 1 diabetes in both the case-control and family collections (odds ratio for AA 1.29 95% CI 1.20-1.37 and relative risk for AA 1.22 95% CI = 1.12-1.32; combined P = 4.3 × 10(-18)), based on a recessive effects model.
Our findings linking FUT2 and type 1 diabetes highlight the intriguing relationship between host resistance to infections and susceptibility to autoimmune disease.
The interacting effects of drought and fire on ecological communities are poorly understood. Long-term studies in the Warrumbungle Mountains, central-west New South Wales, subject to drought and fire ...during the past 21 years, enabled their separate and combined effects to be quantified for individual species and functional groups. Insectivores (especially ground-foragers) dominated previous lists of declining species in this region of NSW and were also prominent in the present work. Insectivores were more likely to be drought- than fire-affected, with seven species declining due to drought, three to drought plus fire, and three to fire alone. Our analyses also revealed declines in a suite of honeyeaters (Meliphagidae), previously not reported as declining. Honeyeaters are major pollinators of eucalypts, so the loss of nectarivores and insectivores has far-reaching implications for pollination, recruitment, successional dynamics, and forest health. Four honeyeater species were adversely affected by drought, five by fire, and one by a combination of drought and fire. Drought and fire, alone or in combination, were implicated in declines of granivores, including the Crimson Rosella Platycercus elegans, and frugivores, especially the Mistletoebird Dicaeum hirundinaceum, the latter reflecting the loss of mistletoes in fire-affected landscapes, and foreshadowing additional losses due to the reliance on mistletoe by many species. Another group not previously identified as threatened, but declining due to drought were two omnivores, the Pied Currawong Strepera graculina and Australian Raven Corvus coronoides. Hollow-nesting birds including two species of treecreeper and the Laughing Kookaburra 'Dacelo novaeguineae' fared badly. Several common Australian species were among the decliners, including Laughing Kookaburra, Willie Wagtail 'Rhipidura leucophrys' and Australian Magpie 'Cracticus tibicen'. We conclude that no suite of birds is exempt from these environmental stressors, and predict that, as droughts reduce populations at regional scales and fires diminish carrying capacity of critical habitats at landscape scales, rarer species will decline to local extinction while more commonly observed species will be reduced in abundance.
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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