The immunological consequences of metabolic drug activation by dendritic cells. (360G-Wellcome-078598_Z_05_Z)
Drug hypersensitivity is an important problem during drug development and in the clinic. The immune system is thought to be involved in the pathogenesis, although the key steps leading to drug-specific T cell activation have not been fully elucidated. The aim of the proposed research is to test the hypothesis that metabolism of compounds within dendritic cells can be an important step in the immunopathogenesis of drug hypersensitivity. This will involve characterisation of (a) stable and chemically reactive metabolite formation in dendritic cells; (b) co-stimulatory and antigen-specific interactions between dendritic cells and T-cells; and (c) whether this is altered in hypersensitive patients. The studies will be undertaken using sulfamethoxazole as a paradigm because of its well characterised clinical, toxicological and metabolic profile.Dendritic cell metabolism will be evaluated using a combination of established bioanalytical and immunological techniques. To explore the relationship between metabolism and dendritic cell activation, drug-treated cells will be analysed using immunological and molecular approaches such as flow cytometry, ELISA, EMSA and focussed microarrays. Moreover, the interaction between dendritic cells and T-cell clones from patients will be evaluated using established cell culture methodologies. This integrated approach will provide insight into how drugs can cause tissue injury in man.
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Grant Details
Amount Awarded | 204727 |
Applicant Surname | Naisbitt |
Approval Committee | Physiological Sciences Funding Committee |
Award Date | 2005-12-31T00:00:00+00:00 |
Financial Year | 2005/06 |
Grant Programme: Title | Project Grant |
Internal ID | 078598/Z/05/Z |
Lead Applicant | Dr Dean Naisbitt |
Other Applicant(s) | Prof Kevin Park, Prof Sir Munir Pirmohamed |
Partnership Value | 204727 |
Planned Dates: End Date | 2009-04-30T00:00:00+00:00 |
Planned Dates: Start Date | 2006-04-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | North West |