The role and treatment potential of natural killer T cells in patients with upper gastrointestinal cancer
Sepsis is a life-threatening syndrome that occurs in patients following infection or injury. It is characterised by a hyperinflammatory response in its early stages, which is followed by a profound immunosuppression and multi-organ dysfunction. Sepsis is thought to affect 18 million people worldwide every year with an average mortality rate of 28%, making it a bigger killer than acute coronary disease or any cancer. Natural killer (NK) and gamma/delta T cells that express the Vδ2 T cell receptor (Vδ2 T cells) are important early determinants of immunity and immunosuppression. Alhanouf was awarded a grant from the Royal Embassy of Saudi Arabia to investigate if circulating NK cell and Vδ2 T cell numbers, functional activities and energy requirements are altered in patients with sepsis and to attempt to restore normal function using chemical inhibitors of components of energy metabolism. To date, she has shown that the frequencies of circulating NK cells, but not Vδ2 T cells, are higher in patients with sepsis compared to control subjects and show evidence of increased cytotoxic activity but an impaired ability to produce inflammatory cytokines. Alhanouf is currently characterising the mechanisms by which NK cells and Vδ2 T cells from sepsis patients and control subjects generate energy by measuring changes in the expression of components of energy metabolism in response to cell activation in vitro in the absence and presence of chemical inhibitors of glycolysis and oxidative phosphorylation. It is hoped that the results will identify novel strategies for modulating the immune responses of these cells that may in future be exploited for the treatment of sepsis.
The roles and treatment potential of innate lymphocytes in neonatal brain injury
Neonatal brain injury (NBI) has many causes and can result in significant neurological morbidity such as cerebral palsy. The prevalence of NBI is more than 3.8 per 1,000 live term births. Cooling therapy is the only established treatment but 50% of babies treated will die or have disability and so new therapies to reduce brain injury are urgently needed. The immune system is thought to play a role in the pathogenesis of NBI. Enhanced inflammatory responses are seen in affected infants and in an animal model of NBI. This inflammatory phenotype may be amenable to immunomodulation as an adjunctive therapy to hypothermia. Nawal has been awarded a grant from the Embassy of Libya to study the potential role of innate lymphocytes in the pathogenesis of NBI. Innate lymphocytes are key components of the immune system in neonates, whose adaptive immune systems have not yet developed. They respond rapidly by killing infected cells, by secreting immunostimulatory and immunoregulatory cytokines, and by providing direct help for the activation and differentiation of other cells of the immune system. The hypothesis underlying Nawal’s research is that subsets of innate lymphocytes control the inflammatory responses that contribute to NBI and that immunological interventions that target these cells will serve as adjunct therapies to hypothermia. To date, Nawal has found evidence that subsets of innate lymphocytes are depleted from babies and school-age children with NBI compared to age-matched control subjects. She is currently investigating their functional activities under a variety of conditions to determine if modulators of these cells have the potential to treat the inflammatory responses that underlie the pathogenesis of NBE.Paediatrics
The influence of nutritional status on clinical, immunological and pharmacological outcomes of antiretroviral therapy for HIV-infected children in Uganda
Human immunodeficiency virus (HIV) is a global pandemic that has claimed 39 million lives since the first documented case in 1981. Currently, 36.7 million people, including 3.3 million children, worldwide are living with HIV and over 70% of cases affect people in sub-Saharan Africa, where malnutrition is a significant co-morbidity. As part of a multidisciplinary programme of research funded by Irish Aid and the Higher Education Authority (NOURISH), Judy is investigating the influence of diet, nutritional status and nutritional supplementation on the outcomes of antiretroviral treatment (ART) in children with HIV infection in Uganda, a country where 1.5 million people are positive for the virus. By performing a series of dietary, socio-economic, amphopometric and clinical assessments of a cohort of HIV-infected children and in-depth analyses of biochemical, nutritional, immunological and pharmacological status of blood and urine samples taken over a 12-week period following the initiation of ART, she is identifying critical factors that predispose these children to favourable responses to ART. It is hoped that the results of Judy’s research will inform national policy to optimally administer nutritional supplementation to HIV-infected children receiving ART.Nutrition and Treatment Outcome: Development of a Ugandan - Irish HIV/Nutrition Research Cluster
The influence of nutritional status and nutritional supplementation on clinical, immunological and pharmacological outcomes of antiretroviral therapy for adults in Uganda
Human immunodeficiency virus (HIV) is a global pandemic that has claimed 39 million lives since the first documented case in 1981. Currently, 36.7 million people, including 3.3 million children, worldwide are living with HIV and over 70% of cases affect people in sub-Saharan Africa, where malnutrition is a significant co-morbidity. As part of a multidisciplinary programme of research funded by Irish Aid and the Higher Education Authority (NOURISH), Bernard (Ben) is investigating the influence of diet, nutritional status and nutritional supplementation on the outcomes of antiretroviral treatment (ART) in adults with HIV infection in Uganda, a country where 1.5 million people are positive for the virus. He first performed a series of dietary, amphopometric and clinical assessments of a cohort of HIV-infected adults. He then conducted a randomised intervention in the moderately-malnourished patients, with one group given a daily ready-to-use therapeutic food (RUTF) in addition to ART for 12 weeks and a second group receiving ART alone. Blood samples were taken for biochemical, nutritional, immunological and pharmacological studies to investigate the benefits of RUTF supplementation on disease outcome. It is hoped that the results of Ben’s research will inform national policy to optimally administer nutritional supplementation to HIV-infected adults receiving ART.Nutrition and Treatment Outcome: Development of a Ugandan - Irish HIV/Nutrition Research Cluster
Peptide presentation by CD1d to natural killer T cells
PI: Derek Doherty and Andreas Solomos
CD1d is a major histocompatibility complex class I-like molecule found on a number of cell types that is capable of presenting glycolipid antigens to natural killer T (NKT) cells. Therapeutic activation of NKT cells with glycolipid antigens in mice can prevent and reverse tumour growth and clinical trials involving NKT cell activation are ongoing in humans with various cancers. While the reactivity of NKT cells against glycolipid antigens is well-documented, a small number of reports have provided evidence that NKT cells can also recognise peptides presented by CD1d. In a project funded by the biotechnology company ImCyse, Andreas is evaluating the capacity of a number of peptides derived from tumour antigens to bind to CD1d and to activate the anti-tumour activities of human NKT cells in vitro. It is hoped that this research will lead to the identification of amino acid sequence motifs that can optimally activate NKT cells to promote anti-tumour immunity in humans.ImCyse
The roles of interleukins 12 and 23 and their receptors in the pathogenesis of sepsis
Sepsis is a life-threatening syndrome that occurs in patients following infection or injury. It is characterised by a hyperinflammatory response in its early stages, which is followed by a profound immunosuppression and multi-organ dysfunction. Sepsis is thought to affect 18 million people worldwide every year with an average mortality rate of 28%, making it a bigger killer than acute coronary disease or any cancer. Previous studies from us and others have demonstrated abnormal cytokine levels in patients who develop sepsis. In particular, two cytokines interleukins 12 and 23 (IL-12 and IL-23), which promote immunity against intracellular and extracellular pathogens, respectively, appear to be dysregulated in sepsis patients. In a project funded by the college of Anaesthesia in Ireland, JD is using multicolour flow cytometry to enumerate and phenotype conventional and unconventional circulating lymphocyte subsets, in patients with bacterial sepsis, bacterial infection without sepsis and healthy donors. In particular, he is quantifying the expression of the receptors for IL-12 and IL-23 on each cell type in attempt to identify the downstream targets of dysregulated IL-12 and IL-23 production. Since, the IL-12 and IL-23 receptor signalling pathways are amenable to pharmacological modulation, it is hoped that this project will identify therapeutic targets for sepsis patients.
The roles of innate lymphoid cells and innate T cells in the pathogenesis of small vessel vasculitis
Anti-neutrophil cytoplasm antibody-associated vasculitis (AAV) refers to a group of severe multisystem autoimmune diseases affecting the microvasculature. This encompasses microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, formally known as Wegener’s granulomatosis) and eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome). AAV is characterised by relapsing necrotizing vasculitis of small blood vessels, frequently involving the kidneys and lungs. Substantial clinical and experimental evidence indicates that the disease pathogenesis is driven by autoantibodies that target components of neutrophils. In this study, funded by Science Foundation Ireland, Ana and Barbara are using multicolour flow cytometry to enumerate innate lymphocyte populations, such as innate lymphoid cells, γδ T cells, invariant natural killer T cells and mucosal associated invariant T (MAIT) cells, which are emerging as important effectors of innate immunity, in patients with the different manifestations of AAV. To date, they have shown that the frequencies of MAIT and ILC2 cells are significantly lower in all groups of AAV patients compared to healthy subjects and remain low during remission. However, these cells were also found to be depleted in a disease control group, comprising patients with non-autoimmune kidney diseases, suggesting that these phenotypic changes are non-specific manifestations of renal inflammation rather than being pathogenic in AAV.Renal Inflammation Group
Therapeutic outcomes, immunological responses to treatment and vaccine preventative strategies for Hepatitis C in HIV seropositive individuals
Hepatitis C virus (HCV) is estimated to affect approximately 180 million people worldwide. Because of shared routes of transmission, co-infection with human immunodeficiency virus (HIV) infection is common. In recent years the arrival of direct-acting antiviral agents (DAAs) has markedly improved the therapeutic landscape for patients with HCV. Ciaran is interested in examining the treatment outcomes for HIV/HCV-co-infected patients treated with traditional interferon-based therapy and, more recently, with interferon-free DAA-based therapy. Ciaran is also examining alterations in the innate IFN-α JAK-STAT signaling pathway as a result of HCV treatment initiation in HIV/HCV co-infected patients in order to obtain a further understanding of the complex interaction between HCV and the immune system. Finally, Ciaran has evaluated the safety and immunogenicity of a novel vaccine strategy for HCV, delivered in a prime-boost regimen, in HIV seropositive patients in a Phase I study. This vaccine work is supported by an EU Framework Program 7 grant.
The liver neighbourhood watch: the protective effects of regulatory tissue-resident natural killer (NK) cells against liver decompensation in patients with chronic liver disease
PI: Mark Robinson and Grainne Jameson
Liver cirrhosis is the end-stage of a range of different chronic liver diseases including viral hepatitis, fatty liver disease, and alcoholic liver disease. The clinical management of patients with liver cirrhosis is limited by the lack of prognostic markers that predict disease progression and the lack of therapeutics that block the progression of liver cirrhosis. Definition of the biological mechanisms that contribute to the progression of liver cirrhosis will provide novel prognostic markers and therapeutic agents. While previous studies have described systemic inflammation in peripheral blood samples from cirrhotic patients, it is unclear how this inflammation affects tissue-resident immune cells present within the liver and how this results in deteriorating liver function. We have recently described an abundant population of liver-resident natural killer (NK) cells in humans which are functionally distinct from peripheral blood NK cells. Preliminary evidence suggests this population of liver-resident NK cells plays an important immune regulatory role. In this study, we aim to elucidate the effects of cirrhosis on liver-resident NK cell functions, and through international academic collaborations, define the immune interactions that influence the sensitivity of hepatocytes to apoptotic signals (utilising novel 2D and 3D liver cell culture models). These signals represent potential novel prognostic biomarkers and novel therapeutic targets for patients living with liver cirrhosis. This project involves close clinical collaborations with the National Liver Transplant Unit at St. Vincent’s University Hospital, as well as specialist hepatology centres with St. James’s Hospital, St. Vincent’s University Hospital, and the Mater Misericordiae University Hospital.