Exposure to the antimicrobial peptide LL-37 produces dendritic cells optimized for immunotherapy

Immunization of patients with autologous, ex vivo matured dendritic cell (DC) preparations, in order to prime antitumor T-cell responses, is the focus of intense research. Despite progress and approval of clinical approaches, significant enhancement of these personalized immunotherapies is urgently needed to improve efficacy. We show that immunotherapeutic murine and human DC, generated in the presence of the antimicrobial host defense peptide LL-37, have dramatically enhanced expansion and differentiation of cells with key features of the critical CD103 + /CD141 + DC subsets, including enhanced cross-presentation and co-stimulatory capacity, and upregulation of CCR7 with improved migratory capacity. These LL-37-DC enhanced proliferation, activation and cytokine production by CD8 + (but not CD4 + ) T cells in vitro and in vivo. Critically, tumor antigen-presenting LL-37-DC increased migration of primed, activated CD8 + T cells into established squamous cell carcinomas in mice, and resulted in tumor regression. This advance therefore has the potential to dramatically enhance DC immunotherapy protocols

Starship:Study of Telomeres and Role of Sex Hormones in Pulmonary Fibrosis

RATIONALE Pulmonary fibrosis is an interstitial lung disease (ILD) feature with no curative (other than lung transplantation) or preventative treatments. Recent evidence supports a causal role of short telomeres, and our pre-print findings suggest a potentially protective interaction between optimised sex hormone concentration (testosterone and oestrogen) in men and women and telomere maintenance pathways1. Sex hormone bioavailability is regulated by sex hormone binding globulin (SHBG) in both sexes. Supra-physiological dosing of testosterone in men causes erythrocytosis, so monitoring of haemoglobin concentration and haematocrit is required. STARSHIP set out to assess whether future therapeutic trials of sex hormone supplementation in ILD could be safe and warranted without causing supra-physiological dosing. METHODS Venepuncture was performed on 102 outpatients (age 49-89y, male n=80 [78%]) with fibrotic ILD a ta single regional centre in the UK. Age and sex-matched control samples were obtained from the Exeter 10,000 (EXTEND) biobank. Blood leukocyte telomere length (LTL; measured using high-throughput single telomere length analysis) and sex hormone/SHBG concentrations were determined in all samples. Patients consented for access to their clinical data (including routine pulmonary function). In-depth interviews were carried out by telephone with 93 self-selecting patients, using structured interviews with questions informed by clinical practice, the research team ,and patient partners. RESULTS Almost all male ILD patients (n=77/79) had haemoglobin concentrations and haematocrit below the upper reference limit. Compared to age-matched controls (AMCs) mean LTL was shorter for patients (4.57kb [95%CI: 4.46-4.69] vs 4.78kb [95%CI:4.67-4.89], p<0.006). Mean bioavailable testosterone was lower in male patients (4.95nmol/L[95%CI: 4.50-5.41] vs 6.40nmol/L [95%CI: 5.82-6.98] in AMC; p<0.0001, n=80). Oestrogen concentrations were low for both female patients and controls in keeping with their post-menopausal age, with higher SHBG concentrations for patients (mean 73.7nmol/L [95%CI: 58.6-88.9] vs 52.9nmol/L [95%CI: 42.0-63.8] in AMC; p=0.022). Mean free androgen index (FAI) was below the reference range for female patients (mean 0.51 [95%CI: 0.35-0.67] vs 1.23 [95%CI: 0.77-1.69] in AMC; p= 0.0036, N=22). Both DLCO% predicted (p=0.0005) and FVC% predicted(p=0.005) correlated with bioavailable testosterone concentration in male patients (age-adjusted analysis). FVC% predicted associated with FAI in females (p=0.013) but no association was seen between FAI and DLCO% predicted. CONCLUSIONS Interventional trials of sex hormone supplementation without causing supra-physiological dosing warrant further exploration in patients with ILD

Starship:Study of Telomeres and Role of Sex Hormones in Pulmonary Fibrosis

RATIONALE Pulmonary fibrosis is an interstitial lung disease (ILD) feature with no curative (other than lung transplantation) or preventative treatments. Recent evidence supports a causal role of short telomeres, and our pre-print findings suggest a potentially protective interaction between optimised sex hormone concentration (testosterone and oestrogen) in men and women and telomere maintenance pathways1. Sex hormone bioavailability is regulated by sex hormone binding globulin (SHBG) in both sexes. Supra-physiological dosing of testosterone in men causes erythrocytosis, so monitoring of haemoglobin concentration and haematocrit is required. STARSHIP set out to assess whether future therapeutic trials of sex hormone supplementation in ILD could be safe and warranted without causing supra-physiological dosing. METHODS Venepuncture was performed on 102 outpatients (age 49-89y, male n=80 [78%]) with fibrotic ILD a ta single regional centre in the UK. Age and sex-matched control samples were obtained from the Exeter 10,000 (EXTEND) biobank. Blood leukocyte telomere length (LTL; measured using high-throughput single telomere length analysis) and sex hormone/SHBG concentrations were determined in all samples. Patients consented for access to their clinical data (including routine pulmonary function). In-depth interviews were carried out by telephone with 93 self-selecting patients, using structured interviews with questions informed by clinical practice, the research team ,and patient partners. RESULTS Almost all male ILD patients (n=77/79) had haemoglobin concentrations and haematocrit below the upper reference limit. Compared to age-matched controls (AMCs) mean LTL was shorter for patients (4.57kb [95%CI: 4.46-4.69] vs 4.78kb [95%CI:4.67-4.89], p<0.006). Mean bioavailable testosterone was lower in male patients (4.95nmol/L[95%CI: 4.50-5.41] vs 6.40nmol/L [95%CI: 5.82-6.98] in AMC; p<0.0001, n=80). Oestrogen concentrations were low for both female patients and controls in keeping with their post-menopausal age, with higher SHBG concentrations for patients (mean 73.7nmol/L [95%CI: 58.6-88.9] vs 52.9nmol/L [95%CI: 42.0-63.8] in AMC; p=0.022). Mean free androgen index (FAI) was below the reference range for female patients (mean 0.51 [95%CI: 0.35-0.67] vs 1.23 [95%CI: 0.77-1.69] in AMC; p= 0.0036, N=22). Both DLCO% predicted (p=0.0005) and FVC% predicted(p=0.005) correlated with bioavailable testosterone concentration in male patients (age-adjusted analysis). FVC% predicted associated with FAI in females (p=0.013) but no association was seen between FAI and DLCO% predicted. CONCLUSIONS Interventional trials of sex hormone supplementation without causing supra-physiological dosing warrant further exploration in patients with ILD

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease