Lead Researchers: Professor David Wraith and Dr Ye Oo
PhD Student: Naomi Richardson
Establishment: Institute of Immunology and Immunotherapy, University of Birmingham
Naomi Richardson and Professor David Wraith provided an update on their study funded by a CLDF PhD fellowship grant:
Antigen-specific immunotherapy (ASI) can re-instate immune tolerance by ‘re-educating’ the immune system. ASI is now an established treatment approach for a number of allergies, including peanut, insect sting, grass pollen and cat allergies. ASI has also been translated to autoimmune disease clinical trials in multiple sclerosis and Graves’ disease, which have shown disease-modifying effects of treatment. Professor David Wraith, the primary supervisor on this PhD project has been a pioneer in this area of research for over 30 years.
This project is the first application of ASI to Autoimmune Hepatitis (Type 2) in the hope that this will lead to a potential new treatment option. Patients diagnosed with AIH-2 have a severe and progressive form of liver disease driven by the immune system targeting the body’s own liver tissue. AIH-2 is more commonly diagnosed in children or young adults and is less likely to be sufficiently controlled using immunosuppressive drugs. AIH-2 patients possess immune responses against a key liver protein, CYP2D6, which contributes to chronic and persistent liver damage.
To develop a new treatment approach to specifically ‘switch off’ cells targeting liver protein CYP2D6, we investigated the interaction between CYP2D6 and T cells (an essential part of the immune system).
By measuring how much T cells are activated from different individuals, we have learned which specific parts of the protein (peptides) are responsible for stimulating the immune system. It is likely that these play a significant role in AIH-2 disease.
We compared T cell activation patterns between three patient groups: AIH-2 paediatric, AIH-2 adult, AIH-1 adult and healthy blood donors. This revealed two key peptide regions of CYP2D6 which were significantly more potent activators of T cells from the AIH-2 groups. Interestingly, our work also discovered a previously unidentified activatory CYP2D6 peptide region from AIH-1 patients.
We have then further refined these regions to their smallest possible components, T cell epitopes. Previous work from members of the Wraith lab group have determined that when T cell epitope peptides are delivered to T cells in a tolerance-inducing setting, these disease-driving immune cells in fact become deactivated and are no longer able to generate autoimmune disease.
We hope to provide further updates as we learn more.