 Provided by Humphrey Hodgson F Med Sci Sheila Sherlock Chair of Medicine Director Centre for Hepatology Royal Free / Hampstead Vice-Dean and Campus Director Royal Free and University College School of Medicine |
Dame Shelia Sherlock, Research Prize and Lecture The BASL Annual meeting is held each year in early September. One of the highlights of the Annual meeting is the presentation of the Dame Shelia Sherlock research prize and lecture. This prize is awarded annually to recognise the enormous contribution of Dame Shelia Sherlock to the development of Hepatology as a discipline in its own right. Furthermore, Dame Shelia was involved in the foundation of the British Liver Club in 1961 which subsequently evolved into The British Association for the Study of the Liver (BASL). She was one of our past presidents and the first recipient of The BASL Distinguished Service Award. In keeping with Dame Shelia’s enthusiasm for fostering young researchers, this eponymous research prize is awarded to those without substantive posts in either medicine or science for their research contributions in the field of Hepatology. Research Prize Award Winners:
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2007 Winner of the Dame Shelia Sherlock Research Medal
Dr Bertus Eksteen
Liver Unit - Queen Elizabeth Hospital,
University Hospitals Birmingham NHS Foundation Trust,
Entero-hepatic lymphocyte homing in the pathogenesis of Primary Sclerosing Cholangitis (PSC.)
Abstract
A pivotal feature of our immune system is the ability to direct and position immune cells in tissues compartments where they are able to find their cognate antigen and assert their functions(1). For example, lymphocytes that are primed to recognise mucosal antigens are induced to preferentially traffic to the gut by dendritic cells (DCs) in mesenteric lymph nodes and Peyer’s Patches. Gut DCs are able to imprint responding T cells with a phenotype which allows them to recognise and respond to gut-specific “address codes”. This imprinting is dependent on the unique ability of gut-derived DCs to convert retinol to retinoic acid which in turn allows transcription of gut homing receptors on primed lymphocytes. The gut homing receptors on lymphocytes are the chemokine receptor, CCR9 and the integrin α4β7, which allow the lymphocyte to respond to the gut-restricted chemokine CCL25 and the α4β7 ligand, Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1). Thus the combination of MAdCAM-1 and CCL25 provides a specific gut “address code” to recruit gut-specific lymphocytes to provide immune surveillance and to initiate inflammation(1).
But what occurs if tissue specificity is lost or if molecules such as MAdCAM-1 and CCL25 are aberrantly expressed? In such a scenario mucosal lymphocytes could potentially be recruited to extra-intestinal sites and cause inflammation outside the gut(2). Extra-intestinal inflammation is often seen in patients suffering from inflammatory bowel disease (IBD) and can generally be divided into diseases which occur either at the same time as flares of bowel inflammation (joint, skin and eye disease) or those that run a course that is independent of inflammation in the bowel (liver disease). It is possible that concurrent extra-intestinal diseases occur as a consequence of inflammatory cytokine release from the inflamed gut but such a mechanism would not explain extra-intestinal liver disease, such as autoimmune hepatitis and primary sclerosing cholangitis (PSC) that develop when bowel inflammation is quiescent or after the bowel has been removed. Hence, it has been our hypothesis that extra-intestinal liver disease in IBD might be explained by aberrant homing of gut lymphocytes to the liver and is the main focus of my research(3).
Our lab had previously shown that PSC is associated with aberrant expression of MADCAM-1 on hepatic endothelium(4) and in my research I have gone on to show that PSC is associated with the recruitment of long-lived mucosal memory T-cells in response to the aberrant expression of MAdCAM-1 and the gut-specific chemokine CCL25(5). CCL25 was only detected in significant amounts in liver tissue from patients with PSC and this aberrant expression results in the recruitment of mucosal T cells expressing α4β7 and CCR9. I was able to show that these cells are memory cells that secrete high levels of IFNγ on stimulation suggesting that they could trigger chronic inflammation when recruited to the liver(5). Although CCR9+ α4β7+ lymphocytes isolated from PSC livers had a phenotype that is identical to mucosal T cells it was still plausible that these lymphocytes had not originated in the gut but had been primed in the hepatic lymph nodes by hepatic DCs that induced aberrant expression of adhesion molecules. This led me to determine whether DCs isolated from the liver of patients with PSC have the ability to induce the gut homing phenotype in responding T and B lymphocytes. Liver DCs were competent in inducing activation and proliferation but were not able to induce a gut-homing phenotype in the absence of exogenous retinoic acid. Thus, confirming the mucosal origins of the α4β7/CCR9+ cells in the liver(6) (and work in preparation).
Only 20% of infiltrating T cells in PSC are α4β7/CCR9+ and thus of mucosal origin but their ability to secrete IFNγ allows them to induce the local expression of the chemokines CXCL9-11. In collaboration with Stuart Curbishley in our lab I have shown that the sustained expression of these chemokines by hepatic endothelium leads to the recruitment of further effector lymphocytes expressing the receptor CXCR3(7). Thus the inflammatory response can be broadened and sustained leading to chronic persistent inflammation and liver damage. Once recruited to the liver effector cells must be positioned in tissues and I have shown that another chemokine receptor, CCR10, is involved in the positioning of mucosal T cells at the biliary epithelium in PSC(8). I was able to show that the ligand for CCR10, CCL28 is secreted by cholangiocytes in response to IL-1β and LPS stimulation and that this chemokine activates the adhesion of CCR10 expressing intrahepatic T cells to VCAM-1 expressed by inflamed cholangiocytes. This interaction is mediated by another integrin α4β1 which I have shown not only provides a localisation signal for effector T cells at the biliary epithelium but also provides a potent NFkB dependent survival signal to keep these effector cells alive and thereby to promote the persistence of inflammation.
Thus I propose a novel hypothesis to explain the extra-intestinal complications of inflammatory bowel disease in which long-lived mucosal memory T cells undergo entero-hepatic recirculation between the liver and gut resulting in hepatitis and liver injury.
1 W. W. Agace, Nat. Rev. Immunol. 6, 682 (2006). 2 A. J. Grant et al., Lancet 359, 150 (2002). 3 D. H. Adams, B. Eksteen, Nat. Rev. Immunol. 6, 244 (2006). 4 A.J.Grant et al., Hepatology 33, 1065 (2001). 5 B. Eksteen et al., J. Exp. Med. 200, 1511 (2004). 6 J. R. Mora et al., Science 314, 1157 (2006). 7 S.M. Curbishley et al., Am J Pathol. 167, 887 (2005). 8 B. Eksteen et al., J. Immunol. 177, 593 (2006).
2006 Winner of the Dame Shelia Sherlock Research Medal
Fiona Oakley
University of Southampton, UK
NF-κB; a therapeutic target in liver disease
Abstract
My research focus is how the transcription factor NF-κB contributes to the development of liver fibrosis and inflammation and using inhibitors of NF-κB as potential therapeutic agents.
Fibrosis
NF-κB is a transcriptional regulator of over 200 genes involved in inflammation, cell survival and disease pathogenesis. Classically NF-κB functions as a heterodimer of p50:p65 subunits to regulate gene transcription. Hepatic Stellate Cell (HSC) activation is a pivatol event in fibrogenesis and represents a long-term change in cell phenotype including persistent expression of proinflammatory proteins and an anti-apoptotic state. We have shown that NF-κB (p50:p65) is persistently up-regulated during HSC activation, this is unusual as induction of NF-κB activity is normally a transient event. Interestingly the elevation of NF-κB activity during HSC activation is accompanied by induction of the transcriptional repressor CBF1.
I reported that CBF1 binds to a specific DNA motif in the regulatory region of the gene encoding IκΒα, the inhibitor of NF-κB. CBF1 stimulates repression of IκBα expression by recruiting enzymes that modify chromatin structure towards a condensed transcriptionally inactive state. This results in persistent down-regulation of IkBα and upregulation of NF-κB that serves to influence the proinflammatory and anti-apoptotic behaviour of the cell.
Apoptosis of activated HSC is now established as a mechanism by which the injured liver clears these profibrogenic cells after wound healing is completed. Failure to clear HSC leads to their persistence and progressive deposition of cross-linked collagens in the liver. Pharmacological blockade of NF-κB, using Gliotoxin and Sulfasalazine has been shown to induce HSC apoptosis in vitro and in vivo and as such may be of therapeutic benefit in promoting reversibility of fibrosis. I identified the IKappaKinase (IKK) complex as a molecular target for stimulating HSC apoptosis. The IKK inhibitor and anti-inflammatory drug sulfasalazine stimulates HSC apoptosis in vitro but when administered in vivo substantially accelerates the rate of recovery of fibrotic liver to a near normal structure. Additionally nerve growth factor (NGF) released by hepatocytes promotes inhibition of NF-κB in HSC leading to apoptosis. Therefore release of NGF from hepatocytes during liver injury may represent an important paracrine loop limiting the HSC-dependent fibrotic response.
This may not be the best long-term therapeutic solution as NGF, Gliotoxin and Sulfasalazine affect other pathways. To limit utility my research focus is targeting NF-κB directly, by understanding how specific phosphorylation events on the p65 subunit of NF-κB regulate inflammation and progression of liver disease. Preliminary data shows that phosphorylation of p65 is increased during HSC activation in vitro and in vivo. Cell permeable peptides that specifically block p65 phosphorylation events induce HSC apoptosis.
Inflammation
I repoted a novel anti-inflammatory and anti-fibrogenic role for the p50 subunit of NF-κB. NF-κB is comprised of homo- or heterodimeric combinations of c-Rel, p65, RelB, p50 or p52. Each subunit has distinct biological properties that may be exploited therapeutically. In response to chronic injury p50 knockout mice over-produce TNF-α and have a profound neutrophilic inflammation that leads to severe fibrosis. This work showed that p50 homodimers protect the liver from excessive inflammation by repressing TNF-α gene transcription and recruiting chromatin modifying histone deacetylases to the TNF-α promoter. Stimulating the interaction between p50/HDAC1 at the TNF-α promoter could limit liver inflammation and severity of fibrosis.
Therefore targeting signaling events downstream of the IKK’s i.e. preventing p65 serine 536 phosphorylation could inhibit pro-inflammatory events of IKK signaling but leave the anti-inflammatory pathway unimpaired, providing a novel target for the treatment of liver disease.
