The effect of ageing on immunity; chronic inflammation; cancer; stress and immunity
As humans age they become more susceptible to infectious diseases (especially bacterial infections), inflammatory disease and have poorer responses to vaccinations. Although ageing is a complex process, these data suggest that immune function may be reduced during ageing and will contribute to the increased morbidity of the elderly. Professor Lord’s team has shown that neutrophil function declines with age, specifically that neutrophil phagocytosis of bacteria is reduced by almost half. More recently they have been carrying out studies to determine if this reduced neutrophil function has an impact upon immunity in the elderly and more particularly whether stress accelerates this loss of neutrophil function and makes the elderly more susceptible to infection. The group is investigating a variety of stresses that are common in old age, specifically the physical stresses of hip fracture and loss of sleep and emotional stress imposed by depression or bereavement. Her research so far has shown that after hip-fracture or bereavement, the loss of neutrophil function is dramatically increased and almost half of hip fracture patients succumbed to serious bacterial infections. Importantly this work has revealed that this may be mediated by an excess of the immune suppressive stress hormone cortisol and a lack of the immune enhancing counter stress hormone dehydroepiandrosterone (DHEA). Professor Lord is now seeking funding to try and supplement hip fracture patients with DHEA to see if the number of infections in these patients can be reduced. This research is funded by grants from the BBSRC and ESRC (hip fracture studies), Research into Ageing and the European Union (Sleep and Immunity in old age) and the Dunhill Medical Trust (Bereavement and Immunity).
During an immune response inflammatory cells, including T cells and neutrophils, are recruited to sites of infection to help to clear pathogens. Once the site is rendered sterile these same cells must be removed efficiently to avoid non-specific attacks on healthy tissue. This is achieved in part by their death by apoptosis and removal by macrophages. We have shown that this process is dysregulated in chronic inflammatory diseases such as Rheumatoid arthritis, leading to the accumulation of inflammatory cells and destruction of healthy tissue by cells such as neutrophils. Together with Professor Chris Buckley of the department of Rheumatology, the group is trying to define the mechanisms that regulate the survival and activity of neutrophils and T cells within the inflamed joint, in order to identify new therapeutic targets and strategies for Rheumatoid Arthritis. The group has already identified signals from stromally derived cytokines (type 1 Interferon and GM-CSF) as regulators of neutrophil survival and stromal fibroblasts are now recognised as rational targets in rheumatoid arthritis. This work is funded by a programme grant from the Arthritis Research Campaign.
With funding from the European Union Professor Lord has gone on to use a small molecule library screening approach to identify novel small molecules that are able to regulate neutrophil survival and synovial fibroblast inflammatory function and proliferation (see http://www.proteinkinase-research.org). This has been a productive study which has already identified two novel agents that have reduced inflammation in animal models and work is now ongoing to develop these drugs towards clinical trial.
The third aspect of Professor Lord’s research relates to the search for novel treatments for leukaemia, with a specific focus on targeting the Protein Kinase C family. The PKC family consists of 11 isoenzymes that play different roles in the regulation of cell function and Professor Lord has a particular interest of PKC-delta, which plays a key role in regulating cell survival. She has attempted to identify compounds from natural sources that will modulate the activity of this enzyme, inducing apoptosis in leukaemic cells. Recently she has been working with an Australian biotech company Peplin Ltd (www.peplin.com) to take a plant compound, Ingenol 3-angelate (PEP005) through pre-clinical development for acute myeloid leukaemia. Her work has shown that this agent activates PKC-delta and induces cell death (apoptosis) in AML cells at very low doses. Other work in the group has used a small molecule screening approach to identify novel modulators of PKC activity and this has recently yielded a compound which induces apoptosis in chronic lymphocytic leukaemia cells. This agent has been patented jointly with the University of Helsinki and is now undergoing pre-clinical testing. This work has been funded by a 5 year European commission FP6 integrated project and by Peplin Ltd.
Janet discusses her work into Stem Cells and Ageing in this podcast:
Khanfer RS, Phillips AC, Carroll D, Lord JM (2010). Altered human neutrophil function in response to acute psychological stress. Psychosom. Med.72:636-40.
Curnow SJ, Fairclough M, Schmutz C, Kissane S, Denniston AKO, Nash K, Buckley CD, Lord JM, Salmon M (2010). Distinct Types of Fibrocyte Can Differentiate from Mononuclear Cells in the Presence and Absence of Serum. PLOS ONE 5 (3):e9730.
Hampson P, Wang K, Milverton L, Ersvaer E, Bruserud O, Lord JM (2010). Kinetics of ERK1/2 activation determine sensitivity of acute myeloid leukaemia cells to the induction of apoptosis by the novel small molecule Ingenol 3-Angelate (PEP005). Apoptosis15:946-955.
Arranz L, Lord JM, De la Fuente M (2010). Preserved ex vivo inflammatory status and cytokine responses in naturally long-lived mice. AGE. 32:451-466.
Arranz l, Caamano J, Lord JM, De la Fuente M (2010). Preserved immune functions and controlled leukocyte oxidative stress in naturally long-lived mice: Possible role of nuclear factor-kappaB. J Gerontol Biol Sci Series A. 65:941-950.65941-950.
Phillips AC, Carroll D, Gale CR, Lord JM, Arlt W, Batty GD (2010). Cortisol, dehydroepiandrosterone sulphate, their ratio and all-cause and cause-specific mortality in the Vietnam Experience Study. Eur. J. Endocrinol. 163:285-292.
Lee W-Y, Hampson P, Coulthard L, Ali F, Salmon M, Lord JM, Scheel-Toellner D (2010). Novel antileukemic compound ingenol-3angelate inhibits T cell apoptosis by activating protein kinase C theta. J Biol Chem285:23889-23898.
Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM(2010). Aging of the innate immune system. Current Opinion Immunol. 22:507-513.
Carroll D, Phillips AC, Lord JM, Arlt W, Batty GD(2011). Cortisol, dehydroepiandrosterone sulphate, their ratio, and hypertension: Evidence of associations in male veterans from the Vietnam Experience Study. J Human Hypertension 25:418-424.
Khanfer R, Lord JM, Phillips AC (2011) Neutrophil function and cortisol:DHEAS ratio in bereaved older adults. Brain Behavior and Immunity. 25:1182-1186.
Francis N, Wong SH, WangK, YoungSP, DeignerHP, SalmonM, Scheel-ToellnerD, LordJM (2011) Lactoferrin inhibits neutrophil apoptosis via blockade of proximal death receptor signaling events. Biochim Biophys Acta 1813:1822-1826.
Sapey, E. Stockley, J.A. Greenwood, H. Ahmad, A. Bayley, D.L. Insall. R.H., Lord, J.M., Stockley, R.A. (2011) Structural and behavioural changes of peripheral neutrophils in COPD. Am J Respir Crit Care Med. 183: 1176 – 1186.
Verschuur C, Dowell A, Syddall H, Ntani G, Simmonds SJ, Baylis D, Gale CR, Walsh B, Cooper C, Lord JM, Sayer AA (2011) Markers of inflammatory status are associated with hearing threshold in older people: findings from the Hertfordshire Ageing Study. Age and Ageing. doi: 10.1093/ageing/afr140.
Wang K, Hampson P, Hazeldine J, Kryštof V, Strnad M, Pechan P, Lord JM (2012) Cyclin-Dependent Kinase 9 activity regulates neutrophil spontaneous apoptosis. PLoS ONE 7(1): e30128. doi:10.1371/journal.pone.0030128.