PI3K inhibitors in inflammation, autoimmunity and cancer.

The healthy immune system protects against infection and malignant transformation without causing significant damage to host tissues. Immune dysregulation results in diverse pathologies including autoimmune disease, chronic inflammatory disorders, allergies as well as immune deficiencies and cancer. Phosphoinositide 3-kinase (PI3K) signalling has been shown to be a key pathway in the regulation of the immune response and continues to be the focus of intense research. In recent years we have gained detailed understanding of PI3K signalling, and saw the development of potent and highly selective small molecule inhibitors, of which several are currently in clinical trials for the treatment of immune-related disorders and cancer. The role of PI3K signalling in the immune response has been the subject of detailed reviews; here we focus on relevant recent progress in pre-clinical and clinical development of PI3K inhibitors

Multi-tissue DNA methylation age predictor in mouse.

BACKGROUND: DNA methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse. RESULTS: We have generated a comprehensive set of genome-scale base-resolution methylation maps from multiple mouse tissues spanning a wide range of ages. Many CpG sites show significant tissue-independent correlations with age which allowed us to develop a multi-tissue predictor of age in the mouse. Our model, which estimates age based on DNA methylation at 329 unique CpG sites, has a median absolute error of 3.33 weeks and has similar properties to the recently described human epigenetic clock. Using publicly available datasets, we find that the mouse clock is accurate enough to measure effects on biological age, including in the context of interventions. While females and males show no significant differences in predicted DNA methylation age, ovariectomy results in significant age acceleration in females. Furthermore, we identify significant differences in age-acceleration dependent on the lipid content of the diet. CONCLUSIONS: Here we identify and characterise an epigenetic predictor of age in mice, the mouse epigenetic clock. This clock will be instrumental for understanding the biology of ageing and will allow modulation of its ticking rate and resetting the clock in vivo to study the impact on biological age

Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality following allotransplant. Activated donor effector T cells can differentiate into pathogenic T helper (Th)-17 cells and germinal center (GC)-promoting T follicular helper (Tfh) cells, resulting in cGVHD. Phosphoinositide-3-kinase-δ (PI3Kδ), a lipid kinase, is critical for activated T cell survival, proliferation, differentiation, and metabolism. We demonstrate PI3Kδ activity in donor T cells that become Tfh cells is required for cGVHD in a nonsclerodermatous multiorgan system disease model that includes bronchiolitis obliterans (BO), dependent upon GC B cells, Tfhs, and counterbalanced by T follicular regulatory cells, each requiring PI3Kδ signaling for function and survival. Although B cells rely on PI3Kδ pathway signaling and GC formation is disrupted resulting in a substantial decrease in Ig production, PI3Kδ kinase-dead mutant donor bone marrow-derived GC B cells still supported BO cGVHD generation. A PI3Kδ-specific inhibitor, compound GS-649443, that has superior potency to idelalisib while maintaining selectivity, reduced cGVHD in mice with active disease. In a Th1-dependent and Th17-associated scleroderma model, GS-649443 effectively treated mice with active cGVHD. These data provide a foundation for clinical trials of US Food and Drug Administration (FDA)-approved PI3Kδ inhibitors for cGVHD therapy in patients

Study of the Immunomodulatory Properties of Chlamydophila pneumoniae Major Outer Membrane Protein (MOMP) and Peptides Derived From its Amino Acid Sequence in Context With Atherosclerosis Development.

Atherosclerosis is the main underlying cause of cardiovascular disease and stroke, two major health concerns worldwide. Atherosclerotic lesion progression is driven by pro-inflammatory immune responses. Previous reports have indicated that the 40kDa Major Outer Membrane Protein (MOMP) of the gram negative intracellular bacterium Chlamydophila pneumoniae may have immunomodulatory properties and promote a Th2 mediated immune response. This type of response is predominantly antiinflammatory and protective in the context of atherosclerosis. Therefore, we studied the effects of rMOMP and MHC class II restricted peptides derived from its amino acid sequence on the immune response and atherosclerosis development. We first characterised the effects of rMOMP and the peptides in vitro by treating murine peritoneal macrophages, alone and in co-culture with T cells, with different concentrations of the antigens. Surface marker expression was measured by flow cytometry, and we found that rMOMP, Peptide 3 and Peptide 4 prevented activation of macrophages while Peptides 3 and 4 also prevented T cell activation and induced a regulatory T cell (Treg) phenotype. In vivo studies in C57B1/6 wt and apoE-/- mice showed that immunisation with Peptides 2-4 induced FoxP3+ Treg and IL-10 secretion after 6 weeks. In addition, during 12 week immunisation protocols in apoE-/- mice, Peptides 2-4 increase plasma levels of IL-4, IL-10, TGF-β and IFNγ. Histological analysis of aortic sinus sections from immunised animals showed that rMOMP increased collagen and elastin deposition in the plaque, which indicates a more stable plaque phenotype, while Peptide 2 reduced plaque size. Peptides 3 and 4 also reduced plaque size while simultaneously increasing collagen and elastin deposition. Therefore, we conclude that the atheroprotective effects observed for rMOMP and Peptides 2-4 are mediated through immunomodulation and the promotion of a predominantly antiinflammatory response. In addition, Peptides 3 and 4 are strong candidates for further development as potential anti-atherogenic treatments

Study of the immunomodulatory properties of Chlamydophila pneumoniae major outer membrane protein (MOMP) and peptides derived from its amino acid sequence in context with atherosclerosis development

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

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Taha Toros Arşivi, Dosya No: 161/A-Ahmet Taner KışlalıUnutma İstanbul projesi İstanbul Kalkınma Ajansı'nın 2016 yılı "Yenilikçi ve Yaratıcı İstanbul Mali Destek Programı" kapsamında desteklenmiştir. Proje No: TR10/16/YNY/010

Additional file 4: of Multi-tissue DNA methylation age predictor in mouse

Table of Training and Test samples. (XLS 26 kb

The GPCR adaptor protein norbin suppresses the neutrophil-mediated immunity of mice to pneumococcal infection

Streptococcal pneumonia is a worldwide health problem that kills 2 million people each year, particularly young children, the elderly, and immunosuppressed individuals. Alveolar macrophages and neutrophils provide the early innate immune response to clear pneumococcus from infected lungs. However, the level of neutrophil involvement is context dependent, both in humans and in mouse models of the disease, influenced by factors such as bacterial load, age, and coinfections. Here, we show that the G protein coupled receptor (GPCR) adaptor protein norbin (neurochondrin, NCDN), which was hitherto known as a regulator of neuronal function, is a suppressor of neutrophilmediated innate immunity. Myeloid norbin deficiency improved the immunity of mice to pneumococcal infection by increasing the involvement of neutrophils in clearing the bacteria, without affecting neutrophil recruitment or causing autoinflammation. It also improved immunity during Escherichia coli induced septic peritonitis. It increased the responsiveness of neutrophils to a range of stimuli, promoting their ability to kill bacteria in a reactive oxygen species dependent manner, enhancing degranulation, phagocytosis, and the production of reactive oxygen species and neutrophil extracellular traps, raising the cell surface levels of selected GPCRs, and increasing GPCR-dependent Rac and Erk signaling. The Rac guanine-nucleotide exchange factor Prex1, a known effector of norbin, was dispensable for most of these effects, which suggested that norbin controls additional downstream targets. We identified the Rac guanine-nucleotide exchange factor Vav as one of these effectors. In summary, our study presents the GPCR adaptor protein norbin as an immune suppressor that limits the ability of neutrophils to clear bacterial infections

PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner.

Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death world-wide. Antibody-mediated immune responses can confer protection against repeated exposure to S. pneumoniae, yet vaccines offer only partial protection. Patients with Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated a conditional knock-in mouse model of this disease and identify a CD19+B220- B cell subset that is induced by PI3Kδ signaling, resides in the lungs, and is correlated with increased susceptibility to S. pneumoniae during early phases of infection via an antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves survival rates following S. pneumoniae infection in wild-type mice and in mice with activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the severity of S. pneumoniae infection, representing a potential therapeutic target.Wellcome, MRC, BBSR

Class IA PI3Ks regulate subcellular and functional dynamics of IDO1

none35sìKnowledge of a protein's spatial dynamics at the subcellular level is key to understanding its function(s), interactions, and associated intracellular events. Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic enzyme that controls immune responses via tryptophan metabolism, mainly through its enzymic activity. When phosphorylated, however, IDO1 acts as a signaling molecule in plasmacytoid dendritic cells (pDCs), thus activating genomic effects, ultimately leading to long-lasting immunosuppression. Whether the two activities-namely, the catalytic and signaling functions-are spatially segregated has been unclear. We found that, under conditions favoring signaling rather than catabolic events, IDO1 shifts from the cytosol to early endosomes. The event requires interaction with class IA phosphoinositide 3-kinases (PI3Ks), which become activated, resulting in full expression of the immunoregulatory phenotype in vivo in pDCs as resulting from IDO1-dependent signaling events. Thus, IDO1's spatial dynamics meet the needs for short-acting as well as durable mechanisms of immune suppression, both under acute and chronic inflammatory conditions. These data expand the theoretical basis for an IDO1-centered therapy in inflammation and autoimmunity.noneAlberta Iacono , Andrea Pompa, Francesca De Marchis , Eleonora Panfili , Francesco A Greco , Alice Coletti , Ciriana Orabona , Claudia Volpi , Maria L Belladonna , Giada Mondanelli, Elisa Albini , Carmine Vacca , Marco Gargaro , Francesca Fallarino , Roberta Bianchi , Carine De Marcos Lousa , Emilia Mc Mazza , Silvio Bicciato , Elisa Proietti , Francesca Milano , Maria P Martelli , Ioana M Iamandii , Mariona Graupera Garcia-Mila , Judith Llena Sopena , Phillip Hawkins , Sabine Suire , Klaus Okkenhaug , Anne-Katrien Stark , Fabio Grassi , Michele Bellucci , Paolo Puccetti , Laura Santambrogio , Antonio Macchiarulo, Ursula Grohmann , Maria T PallottaIacono, Alberta; Pompa, Andrea; De Marchis, Francesca; Panfili, Eleonora; A Greco, Francesco; Coletti, Alice; Orabona, Ciriana; Volpi, Claudia; L Belladonna, Maria; Mondanelli, Giada; Albini, Elisa; Vacca, Carmine; Gargaro, Marco; Fallarino, Francesca; Bianchi, Roberta; De Marcos Lousa, Carine; Mc Mazza, Emilia; Bicciato, Silvio; Proietti, Elisa; Milano, Francesca; P Martelli, Maria; M Iamandii, Ioana; Graupera Garcia-Mila, Mariona; Llena Sopena, Judith; Hawkins, Phillip; Suire, Sabine; Okkenhaug, Klaus; Stark, Anne-Katrien; Grassi, Fabio; Bellucci, Michele; Puccetti, Paolo; Santambrogio, Laura; Macchiarulo, Antonio; Grohmann, Ursula; T Pallotta, Mari