The immunological consequences of metabolic drug activation by dendritic cells. (360G-Wellcome-078598_Z_05_Z)

£204,727

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