9:45 – 10:00 Introduction by the Chair: Dr Sonia Quaratino, Reader in Immunology, Cancer Research UK Clinical Centre, University of Southampton

10:00 – 10:20 Why use spontaneous models of human disease?
Professor Elizabeth Simpson, Imperial College London
There are many answers to this question, and I will discuss three, emphasizing their strengths but mindful of their weaknesses.
1. Biological processes in complex organisms, especially mammals, have many features in common
2. Many pathological processes in humans are very complex, and as populations are outbred, it is difficult to study sufficient patients to determine the relative importance of each parameter. Genetic and transgenic studies in mice can help to unravel these
3. Some ‘artificial’ models provide information about ‘natural’ regulatory mechanisms for potential therapeutic use

10:20 – 10:40 The NOD mouse model of Type 1 diabetes
Professor Anne Cooke, University of Cambridge, UK
NOD mice spontaneously develop Type 1 diabetes at high incidence. Using this mouse model of the human autoimmune disease we have been able to show that certain infections can inhibit the development of Type 1 diabetes. The ways in which different infections modulate diabetes onset will be presented in this talk

10:40 – 11:10 Mid-morning break

11:10 – 11:30 A novel humanized animal model of spontaneous autoimmune thyroiditis
Dr Ester Badami, Cancer Sciences Division, University of Southampton
TAZ10 transgenic mice express a human TCR specific for Thyroid Peroxidase (TPO), a main thyroid self-antigen. Here we demonstrate that this self-reactive human TCR is positively selected in the thymus and expressed on both CD4 and CD8 T cells. Interestingly, transgenic T cells retain the same antigen specificity for mouse TPO and are activated in vivo, in absence of mouse immunization. Strikingly, we observed that naïve TAZ10 mice spontaneously develop autoimmune hypothyroidism with histological, hormonal and clinical signs similar to the human pathology. TAZ10 mice therefore represent a valid model to elucidate the mechanisms of T cell activation and regulation in human autoimmunity.

11:30 – 11:50 Understanding the Pathogenesis and Treatment of Multiple Sclerosis Through Experimental Models
Professor David Wraith Cellular and Molecular Medicine, University of Bristol
Multiple Sclerosis (MS) is a complex, heterogeneous disease. The HLA association with MS suggests an autoimmune basis. There is, however, evidence to suggest underlying neurodegenerative pathology. Autoimmune encephalomyelitis (EAE) in experimental animals shares many features with MS. EAE has been used to reveal features of immune pathology and has clarified the role of T cells in the initiation, propagation and regulation of disease. The EAE model has been invaluable for assessment of novel treatments for MS and other autoimmune diseases. This talk will critically assess the contribution of EAE to our understanding of MS and its treatment.

11:50 - 12:10 Humanizes spontaneous transgenic models of MS - immunology, imaging and therapeutics
Professor Daniel Altmann Imperial College, London
Multiple sclerosis is thought to involve CD4 T cell recognition of self myelin, many studies focusing on a pathogenic role for anti-myelin, HLA-DR15-restricted T cells. In the mouse EAE model, it is known which epitopes trigger disease and that disease is associated with determinant spread of T cell reactivity.  Characterization of these events in human MS is critical for the development of peptide immunotherapies, yet it has been difficult to define the T cell responses implicated in pathogenesis.   As a means of bridging this gap, we reported humanized transgenic mice, strongly expressing HLA-DR15 with an MS-derived T cell receptor. Even on a RAG-2 wild-type background, mice spontaneously develop paralysis. Disease, involving demyelination and axonal degeneration, correlates with inter- and intra-molecular spread of the T cell response to HLA-DR15 restricted epitopes of MBP, MOG and aB-crystallin.   Disease develops in the face of a  large population of CNS-infiltrating, FoxP3 , IL-10 Tregs. This is accompanied by an increase in local expression TLR2, 4 and 9.  Disease can be tracked non-invasively by MRI, which also reveals extensive cerebral atrophy correlating with neurodegeneration.  This model, encompassing pathologically relevant, spontaneous disease with the presentation of myelin epitopes in the context of HLA-DR15, affords new insights and predictions about T cell responses during MS as well as a more stringent test-bed for immunotherapies. Some of these therapeutic studies will be discussed

12:10 - 12:30 Spontaneous and induced models of rheumatoid arthritis
Dr Richard Williams, Kennedy Institute of Rheumatology, Imperial College London Rheumatoid arthritis is a chronic disabling disease affecting around 1% of the population. Much progress has been made in recent years towards the identification of mediators that contribute to the pathogenesis of rheumatoid arthritis. However, there is still a lack of knowledge of the underlying causes of the disease and it is for this reason, together with the need for more durable remedies, that animal models of arthritis are studied. This talk will discuss the merits and limitations of the available models and will present data from our own laboratory concerning the role of T cells in driving disease chronicity.

12:30 - 13:00 Discussion

13:00 - 14:00 Lunch

14:00 – 14:20 A mouse model for celiac disease
Dr Mauro Rossi Istituto di Scienze dell’Alimentazione, Naples, Italy
Celiac disease (CD), is caused by the lack of oral tolerance to wheat gluten. A central role of CD4 T cells in CD is supported by the identification of gluten-specific intestinal T cells in celiac patients and the strong association with HLA-DQ2 and -DQ8 genes. Studies aimed at identification of therapeutic strategies, have been hindered to date due to the lack of adequate in vivo models. We addressed this issue in DQ8 transgenic mice with intestinal gliadin hypersensitivity. Our data indicated that various factors are needed to induce changes in the mucosal architecture of gliadin-sensitised mice, one of them is represented by inhibition of COX-2.

14:20 – 14:40 The myodystrophy mouse; providing insights into the glycobiology of muscular dystrophy
Professor Jane Hewitt, Institute of Genetics, University of Nottingham
The spontaneous mouse myodystrophy mutant is a model for human dystroglycanopathies; congenital forms of muscular dystrophy that are often very severe and are typically associated with neuronal migration defects and eye abnormalities. The myodystrophy mouse has a mutation in the putative glycosyltransferase gene LARGE, resulting in aberrant glycosylation of the extracellular matrix receptor dystroglycan. LARGE is one of six proteins that act in a specific, essential glycosylation pathway for dystroglycan. Null mouse mutants of most of these genes show embryonic lethality; LARGE is an exception and the myodystrophy mouse is providing insights into the biology of these human muscular dystrophies.

14:40 – 15:00 What have we learned from spontaneous animal models of muscular dystrophy
Professor Dominic J Wells, Imperial College London, UK
The mdx mouse and GRMD dog are spontaneous models of DMD. Both lack dystrophin and consequently have unstable muscles that are prone to necrosis. Thus basic physiological and pathological studies of both have helped aid our understanding of DMD. The mouse allows for statistically meaningful studies of different treatment options but is less severely affected by the disease compared to man raising concerns about extrapolating results. The GRMD dog is more severely affected and more closely resembles the human condition. The vital role these two animal models have played in the development of novel therapies will be discussed.

15:00 – 15:30 Afternoon Break

15:30 – 15:50 Molecular Regulation of Lymphocyte Homeostasis
Dr Mike Lenardo, Chief, Molecular Development Section Laboratory of Immunology, NIAID, NIH, USA

15:50 – 16:10 Mouse Models of Arteriosclerosis
Professor Qingbo Xu, BHF John Parker Chair of Cardiovascular Sciences, King’s College London, UK
Attracted by the well-defined genetic systems, a number of investigators have begun to use the mouse as an experimental system for arteriosclerosis research. Hundreds of inbred lines have been established, and the genetic map is relatively well defined. Recently, several mouse models for studying all types of arteriosclerosis have recently been established. Using these mouse models, much knowledge concerning the pathogenesis of the disease and therapeutic intervention has been gained. This presentation will focus on models of arterial injuries, vein grafts, and transplant arteriosclerosis, by which the major progress in understanding the mechanisms of the disease has been made.

16:10 - 16:30 Mouse Models of immunodeficiency and immunopathogenesis by conditional mutagenesis in myelod and lymphod lineages
Dr Jürgen Roes, University College London, UK
Mouse models with well defined mutations are essential to advance our understanding of the molecular mechanisms controlling cellular systems and cause disease when they fail. By cell type-specific mutagenesis (Cre/loxP) of evolutionary conserved regulators such as the Src family kinase Csk (ref1) or the receptor for TGF-beta (refs 2,3), we have not only identified key regulators of leukocyte activation in vivo, but also obtained characteristic disease phenotypes resembling neutrophilic dermatitis or hyper-g-globulinaemia, B cell hyperplasia and IgA-deficiency. While continuing with the analysis of the mechanisms underlying the disease phenotype, we aim to extend the scope of our approach by expanding the range of mouse strains for cell type-specific mutagenesis. Using BAC mediated knock-in of an improved Cre recombinase into candidate gene loci expressed specifically in neutrophils or macrophages we hope to obtain the experimental systems required for the selective dissection of acute or chronic inflammatory responses in vivo.

16:30 – 16:50 The Immunological Disease Continuum- Implications for animal models
Professor Dennis McGonagle, University of Leeds ,UK
Gathering insights into the pathogenic mechanisms of human diseases and immunotherapy development has been hampered by the lack of suitable animal models. Furthermore, the autoimmunity paradigm that has dominated immunology for so long, views inflammation against self in terms of aberrant adaptive immune responses. A clear definition of what constituted non-infectious tissue inflammation that is not autoimmune in origin has not been defined. This has contributed to the development of a number of animal models of autoimmunity that are poor surrogates for their supposed human counterparts. Because of this and based on work into the microanatoimcal basis for inflammatory arthritis localisation in man we have developed the immunological disease continuum of self directed tissue inflammation (McGonagle McDermott PLoS Medicine 2006 e297). According to this scheme classic autoimmune effector mechanisms are at one extreme and tissue specific (autoinflammatory) factors that trigger innate immune activation at the other extreme. Many diseases regarded as autoimmune actually site closer to the innate immune boundary according to this scheme. It appears that tissue specific factors including joint microdamage rather than adaptive immune responses underscores to a large extent disease localisation in some diseases formerly thought to be autoimmune including psoriasis, psoriatic arthritis, ankylosing spondylitis and inflammatory bowl disease and, to a degree, even in rheumatoid arthritis. Such tissue specific factors are also likely to be species specific. The implications of this for an improved conceptual understanding of autoimmunity and for animal model design and interpretation are discussed.

16:50 – 17:20 Discussion and Chairman’s summing up