Emeritus Professor of Immunobiology
Division of Immunology
University of Cambridge
Tennis Court Road
We normally think of the immune system as being beneficial because it fights infection. However, in some situations the immune system can target our own tissues and cause pathology or autoimmune disease. The development of autoimmune disease is influenced by genetic and environmental factors.
The work that is carried out in this laboratory is aimed at:
- 1. understanding the pathological processes and factors influencing the development of autoimmunity
- 2. devising therapeutic strategies
- 3. studying tissue repair processes with a view to ultimately restoring cells destroyed by the autoimmune pathology.
Our studies have largely focused on Type 1 diabetes. In this autoimmune disease the insulin producing pancreatic ß cells are destroyed by the immune system. When an individual develops symptoms of Type 1 diabetes they have already destroyed many of their ß cells (70%). An ideal therapeutic approach would therefore be to permanently halt the autoimmune attack (develop immune tolerance) while preserving the ability to fight infection and also to facilitate the replacement of the destroyed ß cells.
To achieve these goals it is essential to carry out studies using good animal models of this human autoimmune disease. The non obese diabetic (NOD) mouse provides such a model. This mouse spontaneously develops another autoimmune disease, Sjögren's syndrome, as well as diabetes. As in humans, the development of these diseases is governed by genetic and environmental factors. We have used this model extensively to analyse the factors influencing the development, to explore therapeutic strategies and also to examine ways of replacing the destroyed beta cell mass. In collaboration with Dr T Rich (University of Glasgow) we are investigating basic mechanisms underlying onset of autoimmunity. With regard to therapy, our focus is currently on the use of combination therapies involving monoclonal antibodies with the capacity to halt ongoing disease as well as to induce long term tolerance. In terms of islet replacement, we collaborate with Dr Jenny Nichols at the Centre for Stem Cell Research to explore different approaches to replace the destroyed ß cell mass. Key to all of this work is the identification of biomarkers that can be used to predict diabetes onset. We collaborate with Dr Jules Griffin (Biochemistry) to achieve this goal.
Our study of environmental factors has highlighted a key role for infection in reducing the incidence of Type 1 diabetes. We find that protection from diabetes arises through an interaction between the infectious agent and the innate immune system such that circuits which regulate the autoimmune response are reinforced. These studies are carried out in collaboration with Professor D Dunne (Microbiology and Parasitology) and Dr P Mastroeni at the Vet School.
Many genes influence the development of Type 1 diabetes. While some genes such as those encoding MHC class II molecules play a major role other genes have been more difficult to identify. Dr Jenny Nichols and I have generated NOD ES cells and these will be used to identify and characterise genes involved in diabetes development in NOD mice.
- Group Members:
Sarah Gibbs, Steve Newland, Yvonne Sawyer, Maja Wallberg, Paola Zaccone
- Nichols J, Jones K, Phillips JM, Newland SA, Roode M, Mansfield W, Smith A, Cooke A. (2009) Validated germline-competent embryonic stem cell lines from nonobese diabetic mice. Nat Med. 15:814-8.
- Bending D, De La Peña H, Veldhoen M, Phillips JM, Uyttenhove C, Stockinger B, Cooke A. (2009) Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest. 119: 565–572
- Burton OT, Zaccone P, Phillips JM, De La Peña H, Fehérvári Z, Azuma M, Gibbs S, Stockinger B, Cooke A. (2010) Roles for TGF-beta and programmed cell death 1 ligand 1 in regulatory T cell expansion and diabetes suppression by zymosan in nonobese diabetic mice. J Immunol. 185:2754-62
- Bending D, Newland S, Krejcí A, Phillips JM, Bray S, Cooke A. (2011) Epigenetic changes at Il12rb2 and Tbx21 in relation to plasticity behavior of Th17 cells. J Immunol. 186:3373-82
- Cooke A. (2012) Parasitic worms and inflammatory disease. Curr Opin Rheumatol. 24:394-400
- Herold KC, Vignali DA, Cooke A, Bluestone JA. (2013) Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol.13(4):243-56.