Richard Mellanby investigates the factors necessary for dendritic cells to initiate autoimmunity.
An individual’s nutritional status can have a profound impact on their immune system. For example, vitamin D's main physiological role was historically considered to be the maintenance of skeletal health, but following the discovery of vitamin D receptors on immune cells there has been an exponential growth in the number of studies exploring the role of vitamin D and the regulation of the immune system. This interest has been fuelled by the clinical observations that subclinical deficiency in vitamin D is associated with the development and poor outcomes of a wide range of inflammatory disorders. These findings have attracted considerable public interest and the vitamin D supplementation market in the US alone is now estimated to be worth $600 million per annum. Despite the well-established association between low vitamin D status and poor health outcomes, there is considerable uncertainty on the therapeutic benefit of vitamin D supplementation for healthy patients, and how vitamin D shapes the immune response to both pathogens and self-antigens remains poorly understood. The aim of my research programme is to advance understanding on how nutritional status influences the immune response and long term health outcomes.
My research explores the relationship between nutrition, inflammation and health outcomes in companion, farm and wild animals. These studies run alongside mechanistic investigations in murine experimental disease models. This diverse, multi-species approach allows me to address key nutritional research questions which would not be possible using a single species system.
I am currently a Wellcome Trust Intermediate Clinical Fellow examining the factors which antigen presenting cells (APCs) have to provide in order to drive an autopathogenic T cell response. A central theme of this work focuses on how vitamin D modulates the host immune response. I have demonstrated that vitamin D supplementation ameliorates the development of experimental autoimmune encephalomyelitis (EAE) when induced by the administration of an adjuvant and myelin autoantigens. In contrast, I have found that administration of vitamin D does not alter the development of active EAE which arises following the administration of ex-vivo activated myelin responsive T cells. This finding has anchored my long standing research interest on understanding the effects of vitamin D on myeloid cell biology. My research has shown that vitamin D modulates expression of inhibitory molecules, cytokines and chemokine receptor on dendritic cells generated in vitro. The functional relevancy of these protein changes have been probed by gene silencing siRNA techniques, over-expression vectors and a wide range of in vitro and in vivo assays which my lab has developed over the past decade, including a novel model of EAE in which central nervous system autoimmunity develops following the transfer of naïve auto-antigen responsive T cells and APCs loaded with a relevant peptide. This programme of work has been supported by three consecutive Wellcome Trust Fellowship Awards and builds on my previous published research into regulatory T cell biology and the mechanism of T cell tolerance.
I am also leading population-based epidemiological studies which are examining the relationship between vitamin D, inflammation and health outcomes in numerous animal populations. I am studying vitamin D homeostasis in several well-phenotyped sheep flocks and cattle herds based in the UK and overseas from which longitudinal vitamin D metabolite data is available. I am also studying vitamin D metabolism in wild animals, notably an unmanaged Soay sheep flock resident on St Kilda. This programme of work has recently demonstrated a relationship between vitamin D status and fecundity which is the first study to link vitamin D and ecological fitness in wild animals.
I run a parallel translational clinical vitamin D research programme which studies spontaneous vitamin D metabolism disorders in client-owned companion animals. This work has resulted in the clinical validation of parathyroid hormone related protein and vitamin D metabolite assays and led to the description of several novel calcium homeostasis disorders in dogs. I have described a novel syndrome of hypovitaminosis D in dogs with inflammatory bowel disease (IBD). Follow-up studies have demonstrated an association with low vitamin D status and gastrointestinal and systemic inflammation and, importantly, with a poor clinical outcome. This programme of work has expanded into a broader investigation of the relationship between vitamin D biology and a wide range of infectious, neoplastic and allergic disorders in companion animals. A key finding of this work has been the demonstration that low vitamin D status is highly predictive of all-cause mortality in hospitalised cats. In addition, we have demonstrated that steroid resistance in canine atopic dermatitis is associated with hypovitaminosis D.
I graduated from the University of Glasgow in 1998 and after two years in small animal practice I completed a 3 year residency in small animal medicine at the University of Cambridge. I was awarded the RCVS Certificate in Small Animal Medicine in 2001, the RCVS Diploma in Small Animal Medicine in 2003 and the ECVIM Diploma in Companion Animal medicine in 2004. I was then awarded a Wellcome Trust Clinical Training Fellowship to undertake studies into T cell activation and regulation in diabetes at the University of Cambridge for which I was awarded a PhD in 2007. I moved to the University of Edinburgh in 2007 and worked as a clinical fellow dividing my time between clinical work and research. I was awarded a second Wellcome Trust Fellowship to continue my studies into T cell activation in 2008. I was appointed Head of Small Animal Medicine in 2011 and Head of Veterinary Clinical Research in 2012. In 2012 I was awarded a third Wellcome Trust Fellowship to explore how antigen presentation cells activate a pathogenic T cell response. I was promoted to Head of Companion Animal Sciences in 2016 and am currently a Reader in Comparative Medicine.