Community Research and Development Information Service - CORDIS

FP7

ImmunoTension Report Summary

Project ID: 631773
Funded under: FP7-PEOPLE
Country: United Kingdom

Periodic Report Summary 1 - IMMUNOTENSION (Inflammation and Immunity in Human Hypertension and Vascular Dysfunction.)

Hypertension is a major cause of death and disability in Europe and in the rest of the World. It affects 30% of adults, and additional 30% are at very high risk of developing hypertension. It is the main cause of death worldwide according to WHO, accounting for nearly 8 million deaths every year. This is an enormous health problem as it is a cause of subsequent renal failure, stroke, myocardial infarction and heart failure. Despite extensive research, the mechanisms of most cases of hypertension remain unclear. In spite of therapies available, over 40% of treated patients do not reach treatment goals and present with uncontrolled disease. Since the mid-1980s, no new classes of drugs have been successfully developed to treat hypertension. We and others have recently made observations providing a novel mechanism for hypertension involving activation of the immune system, with involvement of T lymphocytes, monocytes and dendritic cells. Mice lacking T cells or monocytes are protected from severe hypertension and renal/vascular dysfunction. Perivascular and renal infiltration of these cells producing cytokines such as IL-17 and TNF-alpha has been implicated. The exact mechanisms or relevance of these observations for human hypertension is unclear. Therefore, we proposed to investigate the involvement of the immune system in human hypertension. First, we proposed to analyse in depth the characteristics of leukocytes in hypertensive patients in comparison to normotensive controls. Subsequently we proposed to focus on leukocytes infiltrating perivascular adipose tissue and cortex and medulla of the kidney in hypertension in relation to detailed clinical phenotypes of the disease such as ambulatory blood pressure monitoring or vascular dysfunction. Subsequently we will perform ex vivo functional studies by co-incubation of reporter vessels with hypertensive T cells (other leukocytes) to examine their role in vascular dysfunction. These interdisciplinary studies of hypertension have the potential of providing a new understanding and possibly treatment of this otherwise devastating disease.
Studies were successfully initiated and in accordance with proposal, T cells were characterised in peripheral blood samples hypertensive patients and normotensive control subjects. The main observation published in our paper in Hypertension (Hypertension, 2016; Jul;68(1):123-32.) was that primarily memory CD4+ and CD8+ circulating T cells are increased in hypertension. In line with experimental data human T cells produce increased IL-17A, IFN-γ and TNFα. In vitro studies performed to complaint these demonstrated that prehypertensive angiotensin II is not sufficient to cause changes in profile of T cell activation, which suggests participation of other hypertension specific factors.
To investigate the mechanisms of local target organ involvement in inflammation we have initiated studies of perivascular and renal T cell infiltration in both models of Ang II induced hypertension and in human samples. In animal models we have demonstrated that chemokine and in particular RANTES (Regulated upon Activation Normal T cell Expressed and Secreted) is critical for the recruitment of CCR5+, CCR1+ and CCD3+ T cells producing IFN-g and TNF-a to perivascular adipose tissue. The overexertion of this chemokine is associated with endothelial and vascular dysfunction in hypertension in humans both locally (perivascular AT in IMA) and in plasma (published in FASEB J, 2016). Moreover RANTES levels are increased at early stages of atherosclerotic disease in humans (published in J Physiol Pharmacol, 2016). We are now continuing characterisation of these cells in human hypertension and aiming to understand the mechanisms of their effects on vascular dysfunction and regulation of blood pressure in patients.
This project so far has enabled to start the development of an internationally competitive research program looking at inflammatory mechanisms of hypertension and its links to vascular dysfunction and disease. PI further developed his expertise through interactions with European immunologists such as the Immunology group at Glasgow (I McInnes). Expected final results will have significant impact on several levels Scientifically it helps to fill in a gap in the understanding of inflammatory mechanisms in human hypertension. Socio-exconomically - hypertension is a major cause of death and disability (renal failure, stroke, myocardial infarction and heart failure) worldwide. Defining new mechanisms of this devastating disease is vital. In summary this project is expected to provide important stimulus for technological development of biomarkers and treatment of hypertension or at least enable understanding if and how inflammatory mechanisms described in animals play a role in humans. The studies described allowed the Fellow to establish independent tenured position at the University of Glasgow as Regis Professor of Physiology and Cardiovascular Pathobiology, attract independent competitive funding and new members of his research group. CIG enabled a good balance between research teaching and other responsibilities.

Contact

Joe Galloway, (Research Support Manager (EU & International))
Tel.: +44 141 330 3884
E-mail

Subjects

Life Sciences
Record Number: 194371 / Last updated on: 2017-02-14
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