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Project Overview:

Rheumatoid arthritis (RA) affects up to 1% of the population worldwide and has a lifetime risk of 4% for women and 2% for men. Conventional treatment choices include corticosteroids and disease modifying anti-rheumatic drugs (DMARDs), which are poorly tolerated in many patients. Patients who fail to respond to DMARDs are generally prescribed TNFα inhibitors, which are not curative and may require years of therapy with the potential for serious adverse events such as infection.

Regulatory T cells play a major role in maintaining self-tolerance by controlling the activity of effector T cells. However, regulatory T cells lose their suppressive ability in active RA and this loss of function is accompanied by reduced expression of key regulatory genes, such as FoxP3 and CTLA-4. We found that reduced FoxP3 and CTLA-4 expression and impaired regulatory T cell function is associated with aberrant CpG methylation and can be reversed by the use of DNA hypomethylating agents.

This project will involve confirmation of these early findings and will include assessment of the long-term tolerogenic capacity and mode of action of DNA methylation inhibitors in animal models of immune mediated disease, with a particular focus on regulatory T cells. Complementary experiments will be performed with cells from human patients and healthy donors to ensure translatability of this therapeutic approach to man. Together, these studies will provide the scientific rationale for a therapeutic strategy for autoimmune disease based around the use of inhibitors of DNA methylation.

Training:

Training will be provided in animal models of autoimmunity, with a focus on arthritis. Full training will also be provided in a range of cell and molecular biology techniques.

Relevant Publications:

  1. Cribbs AP, Kennedy A, Penn H, Amjadi P, Green P, Read JE, Brennan F, Gregory B, Williams RO. Methotrexate restores regulatory T cell function through demethylation of the Foxp3 upstream enhancer in patients with rheumatoid arthritis. Arthritis Rheumatol 2015; 67:1182-92.
  2. Cribbs AP, Kennedy A, Penn H, Read JE, Amjadi P, Green P, Syed K, Manka SW, Brennan FM Gregory B, Williams RO. Regulatory T cell function in rheumatoid arthritis is compromised by CTLA-4 promoter methylation resulting in a failure to activate the IDO pathway. Arthritis Rheumatol 2014; 66:2344-54.
  3. Notley CA, Inglis JJ, Alzabin S, McCann FE, McNamee KE, Williams RO. Blockade of TNFα in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells. J Exp Med 2008; 205:2491-7.
  4. Inglis JJ, Simelyte E, McCann FE, Williams RO. Protocol for the induction of arthritis in C57BL/6 mice. Nature Protocols 2008; 3:612-8.