Guo L.,National Institute of Allergy and Infectious Diseases |
Junttila I.S.,University of Tampere |
Junttila I.S.,Pirkanmaa Hospital District |
Paul W.E.,National Institute of Allergy and Infectious Diseases
Trends in Immunology | Year: 2012
Innate immune and differentiated T cells produce signature cytokines in response to cytokine stimulation. Optimal production requires stimulation by an NF-κB inducer, most commonly an interleukin (IL)-1 family member, and a STAT activator. Usually, there is linkage between the IL-1 family member, the activated STAT and the cytokines produced: IFNγ producers respond to the IL-1 family member, IL-18 and IL-12, a STAT4 activator; IL-13 producers respond to IL-33 (although for ILC2 cells this may be replaced by IL-25) and STAT5 activators; for cells producing IL-17A or IL-22, the combination is IL-1 and a STAT3 inducer. Cytokine-induced cytokine production may have broad significance in orchestrating innate responses to distinct infectious agents and in maintaining inflammatory responses after elimination of the inciting antigen. © 2012.
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-15-2015 | Award Amount: 6.34M | Year: 2015
Stroke is the second leading cause of death in the world population. When not fatal, stroke often results in disability, due to motor and cognitive impairments, and secondary health problems affecting not only patients but also their families. Building on emerging preclinical and pilot clinical evidences, RESSTORE will focus on the clinical assessment of regenerative cell therapy to improve stroke recovery and patients quality of life. RESSTORE European multicentre randomised phase IIb will explore, for the first time, the efficacy (functional recovery) and safety of intravenous infusion of allogenic adipose tissue derived mesenchymal stem cells (ADMSCs) in 400 stroke patients. Therapeutic effects of ADMSCs will be assessed and monitored in patients using clinical rating scales, multimodal MRI and novel blood biomarkers. Additionally, the societal value and cost-effectiveness of ADMSCs-based regenerative therapy will be evaluated through health economics and predictive in silico simulations. Complementary ancillary animal studies will support the clinical trial by defining i) if the treatment response can be further enhanced by intensive rehabilitation, ii) the contribution of co-morbidities and iii) the mechanism(s) underlying the therapeutic effect. The European regenerative therapy capacities (France, Spain, Finland, United Kingdom and Czech Republic), developed in RESSTORE will cover the full value chain in the field (large scale GMP cell production, clinical testing, biomarkers discovery, understanding of the restoring mechanisms, modelling, biobanking, economic studies, exploitation and communication plan). RESSTORE will thus surely contribute, together with the workforce trained in the context of the programme, to improve its public and private (SME) competitiveness and increase the attractiveness of Europe as a reference location to develop and clinically assess new innovative therapeutic options for brain diseases.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.2-1 | Award Amount: 7.86M | Year: 2013
Lipid lowering has significantly reduced cardiovascular disease (CVD) mortality in EU. However, the aim to abolish CVD in EU is far from achieved and attempts to improve on the benefits of statins with new agents have not yet delivered new therapeutics. The Consortium Athero-Flux builds on FP7-generated large-scale lipidomics data showing that specific sphingolipids and in particular distinct ceramides with specific acyl chain lengths are better predictors of CV outcome than traditional risk factors such as low-density lipoprotein-cholesterol. Sphingolipids are implicated in significant biological activities including cell survival, inflammation, and metabolic diseases. Moreover, their levels in metabolic diseases are modulated by previously unrecognized factors such as the gut microflora. Thus, we hypothesize that by controlling sphingolipid metabolism a better primary and secondary prevention of CVD events than with statins alone can be achieved. Athero-Flux builds on cutting-edge SME-led biotechnological tools including: a) high-throughput lipidomic platforms that allow the study of kinetics of lipid metabolism at the molecular lipid level including the new stable isotope labelling technique (Flux); b) whole genome RNA interference screening tools that will allow to identify the regulators of the production of ceramides and the mediators of their biological effect; c) unique locked nucleotide antagonist platforms that have been successfully used clinically in more that 300 patients worldwide. Moreover, it involves Academic partners with top expertise in atherosclerosis, sphingolipid metabolism, and gut microflora to validate targets in the ceramide metabolism. The identification and the validation of the best targets to abate ceramide metabolism though a combination of SME-based leading technology and academia modeling has a strong potential for development of new lipid lowering therapeutics to abate previously unrecognized risk factors for CVD.
Hammaren M.M.,University of Tampere |
Oksanen K.E.,University of Tampere |
Nisula H.M.,University of Tampere |
Luukinen B.V.,University of Tampere |
And 4 more authors.
PLoS Pathogens | Year: 2014
Tuberculosis is still a major health problem worldwide. Currently it is not known what kind of immune responses lead to successful control and clearance of Mycobacterium tuberculosis. This gap in knowledge is reflected by the inability to develop sufficient diagnostic and therapeutic tools to fight tuberculosis. We have used the Mycobacterium marinum infection model in the adult zebrafish and taken advantage of heterogeneity of zebrafish population to dissect the characteristics of adaptive immune responses, some of which are associated with well-controlled latency or bacterial clearance while others with progressive infection. Differences in T cell responses between subpopulations were measured at the transcriptional level. It was discovered that a high total T cell level was usually associated with lower bacterial loads alongside with a T helper 2 (Th2)-type gene expression signature. At late time points, spontaneous reactivation with apparent symptoms was characterized by a low Th2/Th1 marker ratio and a substantial induction of foxp3 reflecting the level of regulatory T cells. Characteristic gata3/tbx21 has potential as a biomarker for the status of mycobacterial disease. © 2014 Hammarén et al.
Hyoty H.,University of Tampere |
Hyoty H.,Pirkanmaa Hospital District
Pediatric Diabetes | Year: 2016
Environmental factors play an important role in the pathogenesis of type 1 diabetes and can determine if a genetically susceptible individual develops the disease. Increasing evidence suggest that among other exogenous agents certain virus infections can contribute to the beta-cell damaging process. Possible viral etiology of type 1 diabetes has been explored extensively but the final proof for causality is still lacking. Currently, the group of enteroviruses (EVs) is considered as the strongest candidate. These viruses have been found in the pancreas of type 1 diabetic patients, and epidemiological studies have shown more EV infections in diabetic patients than in controls. Prospective studies, such as the Type 1 Diabetes Prediction and Prevention (DIPP) study in Finland, are of fundamental importance in the evaluation viral effects as they can cover all stages of the beta-cell damaging process, including those preceding the initiation of the process. DIPP study has carried out the most comprehensive virological analyses ever done in prospective cohorts. This article summarizes the findings from these analyses and discuss them in the context of the existing other knowledge and the prospects for intervention studies with EV vaccines or antiviral drugs. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Turpeinen H.,University of Tampere |
Ortutay Z.,University of Tampere |
Pesu M.,University of Tampere |
Pesu M.,Pirkanmaa Hospital District
Current Genomics | Year: 2013
Members of the substilisin/kexin like proprotein convertase (PCSK) protease family cleave and convert immature pro-proteins into their biologically active forms. By cleaving for example prohormones, cytokines and cell membrane proteins, PCSKs participate in maintaining the homeostasis in a healthy human body. Conversely, erratic enzymatic function is thought to contribute to the pathogenesis of a wide variety of diseases, including obesity and hypercholestrolemia. The first characterized seven PCSK enzymes (PCSK1-2, FURIN, PCSK4-7) process their substrates at a motif made up of paired basic amino acid residues. This feature results in a variable degree of biochemical redundancy in vitro, and consequently, shared substrate molecules between the different PCSK enzymes. This redundancy has confounded our understanding of the specific biological functions of PCSKs. The physiological roles of these enzymes have been best illustrated by the phenotypes of genetically engineered mice and patients that carry mutations in the PCSK genes. Recent developments in genome-wide methodology have generated a large amount of novel information on the genetics of the first seven proprotein convertases. In this review we summarize the reported genetic alterations and their associated phenotypes. © 2013 Bentham Science Publishers.
Tiainen K.,University of Tampere |
Luukkaala T.,University of Tampere |
Luukkaala T.,Pirkanmaa Hospital District |
Hervonen A.,University of Tampere |
Jylha M.,University of Tampere
Age and Ageing | Year: 2013
Background: information about the predictors of mortality among the oldest-old is limited. Also possible gender differences are poorly known. Objective: to examine the predictors of mortality among individuals aged 90 and older, focusing on differences between men and women. We also analysed gender differences in survival at different levels of mobility and activities in daily living (ADL). Design: this 9-year follow-up study is part of the Vitality 90+ study, a population-basedstudy of people aged 90 and older. Subjects: all inhabitants aged 90 and older in the area of Tampere, Finland were contacted, irrespective of health or dwelling place. The study population consisted of 171 men and 717 women. Methods: data werecollected with a mailed questionnaire asking questions concerning ADL and mobility, self-rated health, chronic conditions and socio-economic factors. The participation rate was 79%. Cox regression enter models were used for the analysis. Results: older age, male gender, disability in ADL and mobility, poor self-rated health and institutionalisation increased the risk of mortality in the total study group. In age-adjusted Cox regression models, ADL and mobility were stronger predictors in men than in women (gender interactions, P<0.001). Among those who were partly but not totally dependent in ADL or mobility women survived longer than men. Conclusion: the same health indicators that are important at younger old age alsopredict mortality in the oldest-old. Disability increases the likelihood of death more in men than women. At a very old age, women survive longer with moderate disability than do men. © The Author 2013. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved.
Kondrashova A.,University of Tampere |
Hyoty H.,University of Tampere |
Hyoty H.,Pirkanmaa Hospital District
International Reviews of Immunology | Year: 2014
Type 1 diabetes is caused by an immune-mediated destruction of insulin producing beta-cells in the pancreas. The risk of the disease is determined by interactions between more than 40 different susceptibility genes and yet unidentified environmental factors. The rapidly increasing incidence indicates that these environmental agents have a significant role in the pathogenesis. Microbes have associated with both increased and decreased risk reflecting their possible role as risk or protective factors. Two main hypotheses have been proposed to explain these effects: the hygiene hypothesis suggests that microbial exposures in early childhood stimulate immunoregulatory mechanisms which control autoimmune reactions (analogy with allergy), while the triggering hypothesis suggests that specific microbes damage insulin producing cells. Certain viruses, particularly enteroviruses, are currently the main candidates for such risk microbes. Enteroviruses cause diabetes in animals and have associated with increased risk of type 1 diabetes in epidemiological studies. They have also been detected in the pancreas of diabetic patients. Possible protective effect of microbes has been studied in animal models and in epidemiological studies, where certain enteral microbes (e.g. hepatitis A virus and Helicobacter pylori) and patterns of gut microbiome have associated with low risk of type 1 diabetes. In conclusion, these microbial effects offer attractive possibilities for the development of preventive interventions for type 1 diabetes based on the elimination of triggering agents (e.g. enterovirus vaccines) or use of protective microbes as probiotics. Copyright © 2014 Informa Healthcare USA, Inc.
Huttunen R.,University of Tampere |
Aittoniemi J.,Pirkanmaa Hospital District
Journal of Infection | Year: 2011
Bacteremia and sepsis are major health concerns. Despite intensive research, there are only a limited number of successful treatment options, and it is difficult to see the forest for the trees when considering the pathogenesis of this condition. Studies in the last decade have shown that a major pathophysiologic event in sepsis is the progression from proinflammation to an immunosuppressive state. However, recent genome-based data indicate that sepsis-related inflammatory responses are highly variable, which calls in question the classic two-phase model of sepsis. Adequate and timely antimicrobial treatment is a cornerstone for survival in patients with bacteremia and sepsis. However, microbial resistance has emerged as an increasing challenge for clinicians and with an increasing number of resistant pathogens causing infections, selection of empiric antimicrobial treatment has become difficult. Treatment options currently under way are targeted to enhance immune responses, rebalance the regulation of the dysregulated immune system, remove endotoxin and block/inhibit apoptosis. © 2011 The British Infection Association.
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.4.2-1 | Award Amount: 15.32M | Year: 2008
The health of the EC population has never been better. However, serious public health problems remain, which cannot be ignored including high levels of premature death due to cardiovascular diseases. Thus, new preventive, diagnostic and therapeutic strategies against atherosclerotic cardiovascular diseases are needed. The atherosclerotic changes of the vascular wall are central in the development of cardiovascular complications. The traditional view that atherosclerosis is simply a lipid storage disease has recently been challenged by evidence that inflammation plays a central role in all stages of atherosclerosis. However, molecular mechanisms linking inflammation to atherosclerosis development are not fully understood, and this has severely hampered the advance of diagnostic and therapeutic programs. AtheroRemo aims to identify novel inflammatory mechanisms in vascular remodelling by combining the exploration of human biobanks with animal models and established cellular models. This new knowledge will be used to develop new preventive, diagnostic and therapeutic strategies against atherosclerotic cardiovascular disease. AtheroRemo contains several unique strengths: 1) Outstanding expertise on immunity and inflammation. Our expertise facilitates the breakthroughs in the immuno-inflammatory targeted vascular treatments. 2) Finest European cohorts to search for molecular mechanisms behind atherosclerosis development allowing us to combine underlying genetics with lipidomic profiles in multiple cohorts in order to obtain risk factors and biomarker panel related to inflammatory remodelling. 3) Accelerated target validation with novel liposomal-targeted delivery of nucleic acid-based therapeutics in appropriate animal models. Four SME partners able to exploit the new knowledge support AtheroRemo research. Thus, we expect to translate a number of novel findings into potential clinical applications such as new diagnostic tools (biomarkers) and therapeutics.