Theme 2: Understanding chronic disease

Overview

Overview

Our research in understanding chronic disease is focused on the biology of three critical components of immunity: phagocytes, lymphocytes and stromal cells.

Phagocyte research includes fundamental studies on intracellular organelles (phagosomes and phagolysosomes), responsiveness to chemokines and on antigen presentation. 

Lymphocyte research focuses on the development and function of effector and regulatory T cell populations and the molecular signals that drive them. 

Stromal cells provide the environment in which immune cells operate and our research on stromal cells spans their role in lymphoid organ development through to their role in immunopathology.

Projects

 

Projects

Chemokines

Chemokines and their receptors direct the traffic, positioning and activities of all leukocytes, including mononuclear phagocytes (i.e. monocytes, macrophages and myeloid dendritic cells). While these molecules play an essential role in the recruitment of mononuclear phagocytes during inflammatory responses, the mechanisms by which chemokine stimulation leads to cell activation and changes in functional properties remain largely unclear.

Our research focuses on what is happening inside chemokine-stimulated cells. Using human monocytes- derived cells cultured in vitro, our investigations concentrate on studying the intracellular events taking place following activation of individual chemokine receptors at the cell-surface, and dissecting the underlying molecular mechanisms.


Dendritic cell biology

Dendritic cells play a central regulatory role in immunity, presenting antigen to lymphocytes and de-coding pathogen signals in such a way as to instruct the nature of the ensuing immune response. DCs may also play a role as host cells for some pathogens, facilitating their transpost or providing them with novel means to subvert immune function. Dendritic cell research in the CII includes studies of their cell biology, notably in relation to chemokine receptor function (Signoret Lab), their role in antigen presentation and immune regulation (Kullberg, Kaye and Mountford Labs) and their developmental biology in the context of infectious disease (Kaye Lab).


Immunopathology

Immune-mediated pathology is a feature associated to a greater or lesser extent with all infections. In its mildest form it may give rise to acute manifestations of disease e.g. lymph node swelling, but in extreme cases may itself constitute the major factor leading to clinical deterioration. Research in the CII on immunopathology takes a comparative approach, utilizing acute (Streptococcus, Influenza) and chronic (leishmaniasis, schistosomiasis, Helicobacter) infection models. Collaborative studies with Jon Timmis in the Department of Computer Sciences are aimed at developing computer simulations of complex pathological processes included angiogenesis and granuloma formation.


Mucosal immunology

Intestinal inflammation

Experimental models of intestinal inflammation have helped increase our understanding of clinical disease in humans (Crohn's disease and ulcerative colitis). While the gut flora plays an essential role in disease induction, the mechanisms by which these microbes trigger inflammation is still unclear. The Kullberg Lab is using a model of colitis involving infection with Helicobacter hepaticus (Hh) to study this question.

We have previously characterized both the pathogenic and the disease-protective immune response in hosts that are susceptible versus resistant to Hh-induced colitis. Our studies have demonstrated that the cytokine IL-23 plays an essential role in the development of bacterial-induced colitis, and that a population of IL-10-producing CD4+ T regulatory cells prevent the onset of colitis in disease-resistant hosts. The precise mechanism by which IL-23 contributes to intestinal inflammation is currently unknown; however, this cytokine is known to promote the expansion/maintenance of IL-17A-producing CD4+ Th17 cells that have been implicated in disease pathogenesis in several autoimmune disorders. Moreover, IL-23 can under certain conditions make Th17 cells switch phenotype towards a Th1-like IFN-γ-secreting cell, commonly called an “ex-Th17 cell”. In this regard, we have shown that Hh-induced colitis is associated with elevated frequencies and numbers of intestinal CD4+ T cells secreting IL-17A and IFN-γ, opening up the possibility that the Th17 subset is involved in disease pathogenesis also in the intestinal tract. Ex-Th17 cells do however not seem to be essential for the inflammatory process, as we have found that the degree of Hh-induced colitis is indistinguishable in hosts that can or cannot mount an ex-Th17 cell response to the bacterium.

The lab is interested in understanding how the mucosal immune system senses the bacterial flora, and our goal is to understand the mechanisms by which these microbes trigger pathogenic Th1/Th17 versus disease-protective T regulatory cell responses. In collaboration with colleagues at the University of York, we are also using computational approaches to develop an in silico model of intestinal inflammation (see York Computational Immunology Lab).

Reproductive tract immunology
  • Research group:  Lacey

Work in the Lacey Lab is centered on the development of novel microbicides and vaccines that can be administered by the intra-vaginal route. To further underpin the design of Phase I clinical trials, and in collaboration with the Kaye Lab, we are developing an expanded program of research into the comparative immunobiology of the female genital tract. Current research is focused on defining the function of dendritic cells in the vaginal mucosa and their response to intra-vaginally applied immune modulators and / or microbicides. Novel 3-dimensional organotypic culture systems are being developed, in order to study DC interactions with local stromal cell populations. The roles of FcRn in trans-epithetial transport of IgG and in the regulation of DC function are also being examined. Funding for this research program is currently from the HIV EUROPRISE Network and from the Medical Research Council.

Lung inflammation
  • Research group:  Kaye

Our research in lung inflammation has focused on the biology of alveolar macrophages and the role of gamma delta T cells in the regulation of lung immune homeostasis following Streptococcus pneumoniae infection. Working in the Kaye lab, Alun Kirby has developed novel tools, including targeted microarrays, to evaluate alveolar macrophage responses to lung insult and defined the main features of alveolar macrophage recruitment into the lung. Our data on gamma delta T cells, in collaboration with Simon Carding (UEA) has indicated that these cells play a major role in the regulation of alveolar macrophage numbers during post infection homeostasis. This research programme is funded by the Wellcome Trust.


MicroRNA immunobiology

micro RNA target network

 

MicroRNAs are small non-coding RNAs with a central role in the regulation of gene expression.

 

Our molecular immunology research aims to unravel how microRNAs and their associated RNA-binding proteins function during a cell’s response to infection. We follow an approach that combines the use of human primary cell culture models with relevant in vivo models, and hypothesis-driven functional genomic screens followed by detailed mechanistic studies. Our major goal is to discover novel microRNA-based therapeutics and diagnostics for the treatment of infectious diseases (e.g. leishmaniasis with the Kaye lab, or herpesvirus-associated diseases).


Stromal cell biology

  • Research groups: Kaye

The development and function of the immune system is dependent on interactions between haematopoietic cells and stromal cells. Stromal cells create the microenvironment in which immune system operates providing architectural position and molecular interactions required for normal immune function. Stromal research in the CII include studies on stromal cell development (Coles Lab), stromal cell function in immune responses (Coles, Kaye and Mountford Labs) and stroma in the context of immune pathology (Kaye and Mountford Labs).


Leishmaniasis

 

Leishmaniasis affects approximately 15 million people in 88 countries, results in approximately 100,000 deaths annually, and has a significant impact on health in developing countries. In southern Europe and countries bordering the Mediterranean, leishmaniasis is a major opportunist infection in HIV-infected individuals. Research on leishmaniasis in the Centre is wide ranging and multidisciplinary, including molecular, biochemical and immunological studies.

Research on the immunology of leishmaniasis focuses on disease caused following infection with visceralising species of Leishmania (L. donovani and L. infantum), though comparative research using parasites that cause other forms of disease (cutaneous, mucocutaneous) are also conducted. We have developed novel transgenic lines of Leishmania, that express fluorescent or biophotonic (luciferase) reporter genes and / or defined reporter antigens. These parasites allow us to monitor disease progression non-invasively and by stereo-, confocal and 2-photon microscopy, and to monitor host T cell responses and antigen presenting cell function using TCR transgenic model systems. A major area of research interest is in understanding how immune-mediated pathology contributes to immune-suppression associated with visceral leishmaniasis. Capitalising on the availability of comparative genome sequence data for the major species of Leishmania, we are generating targeted mutant lines to identify survival and virulence factors. Our immunological research into visceral leishmaniasis is funded by Programme Grants from the MRC and the Wellcome Trust. Our vaccine research programme is focused on the development of therapeutic CD8+ T cell-biased vaccines for visceral leishmnaiasis. Funding to develop this work to a first-in-man study in UK volunteers has recently been awarded by the Wellcome Trust.


Schistosomiasis

Dermal immune responses

The research focus of Dr Adrian Mountford's group is the initial host-pathogen interface specifically the induction of innate immune responses by invading schistosome cercariae in the skin, and how cells of the innate immune system affect the priming of acquired T-lymphocyte meditated immunity.

Initial studies revealed that the cytokine environment of the skin (particularly the ratio of IL-12/23p40 : IL-10) is an important factor in the development of protective immune responses induced by the live attenuated vaccine, with dermal-derived CD11c+ and F4/80+ cells being key producers of the protective IL-12/23p40 molecule. Dermal derived IL-10 is also important in regulating the immune response, while CD154 expressed on APCs in the skin is essential for the induction of a Th1-mediated protective immune response. Normal cercariae however induce Th2-type responses particularly following repeat infections. The response is accompanied by an influx of mast cells and eosinophils which leads to the development of 'alternatively-activated' type dendritic cells (DCs) and macrophages. These in turn cause the ensuing adaptive response in the draining lymphoid tissue to be come hypo-responsive.

Investigations of excretory/secretory (E/S) products released by normal cercariae during transformation during skin penetration shows they are the primary source of activating ligands of DCs which drive the development of Th2-type responses. This response is MyD88-dependent, but only partly TLR4-dependent suggesting a role for multiple TLRs in immune activation. Proteomic profiling of these pro-Th2 DCs reveals them to have a 'limited maturation' phenotype rather than a unique Th2-signature proteome. The limited phenotype is associated with changes to cytoskeletal proteins, those involved in cell morphology, and with antigen uptake. Further proteomic analyses by iTRAQ are underway in order to investigate possible changes in membrane associated proteins which has so far identified differential expression of various integrins, MHCII and C-type lectins.

Intestinal immune responses

Whilst the infected host mounts a vigorous inflammatory response to eggs deposited in the liver and intestines following oviposition this response is later down-regulated, resulting in lymphocyte hypo-responsiveness to parasite and third party antigens. Our studies on immune events in the small and large intestine reveal a partial role for 'natural T regulatory CD25+ CD4+ cells' but regulation can also function through the modulated function of antigen presenting cells. We are currently, examining changes in different parts of the gut through a combination of genomic, flow cytometric and microscopy technologies (single and multiphoton confocal microscopy), to pinpoint specific features associated with gene regulation.

The research on the early innate immune response in the skin, and during the chronic infection of the intestines has received support from the BBSRC, The Wellcome Trust, and the European Union via a 6 partner collaboration involving 3 European and 3 African countries. For further information on our EU research see the Schistoinir website.

Research at CII

Featured publication

The Neurotrophic Receptor Ntrk2 Directs Lymphoid Tissue Neovascularization during Leishmania donovani Infection. / Dalton, Jane Elise; Glover, Amy C.; Hoodless, Laura; Lim, Eng Kiat; Beattie, Lynette; Kirby, Alun; Kaye, Paul M.
In: PLOS PATHOGENS, Vol. 11, No. 2, e1004681, 24.02.2015.

Morrison, PJ, SJ Ballantyne, SJ Macdonald, JWJ Moore, D Jenkins, JF Wright, LA Fouser, and MC Kullberg. (2015) Differential requirements for IL-17A and IL-22 in cecal versus colonic inflammation induced by Helicobacter hepaticus. Am J Path 185: 3290-3303.