Translational Gastroenterology Unit
Nuffield Dept Clinical Medicine-Experimental Medicine Division
University of Oxford
John Radcliffe Hospital
Phone: (01865) 220137
South Parks Rd
Phone: (01865) 285494
Fax: (01865) 275591
PhD Studentship at Sir William Dunn School of Pathology in collaboration with Kevin Maloy
The gastrointestinal tract is one of the major sites of immunological challenge to the host immune system. Here the host must be able to mount protective immune responses against invading pathogenic micro-organisms while, at the same time specifically not activating these mechanisms in response to dietary antigens or the beneficial normal enteric flora. In the intestine, therefore, perhaps more than any other organ, immune reactivity must be tightly regulated to ensure induction of protective and not pathologic responses.
The research interests of the group include dissection of the factors that control the mutualistic relationship between commensal bacteria and the intestinal immune system and how this breaks down in inflammatory bowel disease. We have a particular interest in T cell: DC interactions and cytokine networks in the intestine and how these influence the balance between effector and regulatory T cells responses. We combine model systems of intestinal inflammation and colon cancer with the study of innate and adaptive immune responses in inflammatory bowel disease (IBD) patients.
Utilizing models of colitis we have shown that intestinal inflammation is a consequence of a chronic immune response triggered by enteric bacteria. Both innate and adaptive immune mechanisms can cause colitis with elevations of the pro-inflammatory cytokines, IL-6, IFN-g, IL-12/IL-23p40 and TNF-a. Recently, we have re-evaluated the role of IL-12 in orchestrating intestinal inflammation. Strikingly, our new data show that IL-23 and not IL-12 drives intestinal immune pathology. This has also been established for T cell independent innate immune pathology providing the first evidence that IL-23 plays a key role in the innate immune response independent of its effects on T cells.
By contrast with the local immune response, systemic immune activation accompanying T cell-independent colitis was functionally dependent on IL-12 but not IL-23. The differential role of IL-23 in local but not systemic inflammation suggests it may make a more specific target for the treatment of chronic inflammation. Human genome wide association studies have identified common variants of the IL23R gene that confer risk in IBD. Our current research seeks to further understand IL23R mediated innate and adaptive immune pathways in intestinal inflammation and repair. We have collaborative studies with John O'Shea at the NIH to identify STAT-3 targets that are linked to chronic intestinal inflammation.
Patients with IBD are at increased risk of developing colon cancer but little is known about the cellular and molecular pathways that drive tumourigenesis in the intestine. Using a model of inflammation -driven bacteria-induced colon cancer we are performing genetic mapping studies to identify genes that influence the development of colon cancer. We are also studying these pathways in colon cancer patients. This work is part of the EU-funded FP7 Programme INFACARE that brings together a number of European labs working on cellular and molecular pathways in inflammation-driven cancer
Dendritic cells are abundant in the intestine and represent a heterogeneous population of cells that mediate diverse immune functions. In recent work we have identified a distinct subset of DC that express the alpha e integrin and are present at high frequency in the intestine. Under homeostatic conditions CD103+ DC promote regulatory T cell responses via a TGF-beta and retinoic acid dependent mechanism. Current work involves understanding the factors in the intestine that condition DC function and how this changes in inflammation.
Our studies have also shown that functionally specialized populations of regulatory T cells (Treg) play an important role in maintaining intestinal homeostasis. Thus, naturally arising CD4+CD45RBlowCD25+ prevent and most importantly cure intestinal inflammation induced by both adaptive and innate immune responses. These results suggest that stimulation of Treg responses may be beneficial for the treatment of IBD. In response to inflammation Treg cells proliferate in the secondary lymphoid tissue and locally in the intestine suggesting they may act at both sites to curtail the inflammatory response. Mechanistic analysis of Treg-mediated control of colitis showed functional roles for both IL-10 and TGF-b. Expression of CTLA4 on Treg cells themselves also plays an important role. Significantly, like the effector response that drives intestinal inflammation there is also compartmentalization of the Treg response as IL-10 secreting Treg cells are contained at higher frequency in the intestine compared to secondary lymphoid tissue. In addition we have recently shown that the intestine is a site for the development of Foxp3+ Treg cells from naïve precursors and that these cells also contribute to intestinal homeostasis. Our current work focuses on the role of costimulatory pathways in Treg homeostasis in the gut and the specificity and function of distinct Treg subsets in the gut. An understanding of how the body naturally prevents development of inflammatory responses in the intestine may provide important information for the design of immune therapies efficacious for the treatment of a number of autoimmune and inflammatory diseases.
We work closely with Dr Kevin Maloy's lab who works on host-pathogen interactions and innate immune regulation in the intestine: Projects in collaboration with Kevin Maloy (Lab Website).