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The impact of ADAM17 inhibition on L-selectin in murine influenza virus infection

Reed, Sophie 2022. The impact of ADAM17 inhibition on L-selectin in murine influenza virus infection. PhD Thesis, Cardiff University.
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L-selectin (CD62L) is a homing molecule on leucocytes. Previously, Lselectin maintenance on CD8 cytotoxic T lymphocytes (CTLs) improved homing to sites of virus infection and subsequent viral clearance in mouse models of influenza A virus (IAV) infection. This finding led us to believe that L-selectin could be a therapeutic target in viral infection. There are currently no pharmacological agents available which directly block the cleavage of Lselectin, however, ‘A disintegrin and metalloproteinase 17’ (ADAM17) proteolytically cleaves L-selectin from the cell surface. Anti-ADAM17 antibodies were tested for their ability to block shedding of L-selectin in CD8 T cells in vitro, and candidate A9(B8) was chosen to take forward to mouse studies with a 50% maximal inhibitory concentration (IC50) of >261 nM for L-selectin shedding. 10 mg/kg of A9(B8) did not reduce X31 IAV burden in mice over a 7-day infection. 15 mg/kg of A9(B8) was only able to block L-selectin shedding in vivo 6 hours post-administration; this was diminished by 4 days. Transgenic ADAM17 inhibition was then tested in vivo for effects on X31 IAV virus clearance using ADAM17-/- and ADAM17+/+ chimeric mice. Whilst L-selectin was maintained on the cell surface of ADAM17-/- CD8 T cells, these mice did not have reduced X31 titres 5 days post-infection. This timepoint may be too early to investigate T celldependent virus clearance and requires further investigation. Furthermore, ADAM17 chimeras revealed a novel role for ADAM17 in homeostatic shedding of L-selectin in B cells, but not T cells. Further in vitro studies showed that A9(B8) was less effective at blocking L-selectin shedding from B cells than T cells. However, A9(B8) was more effective at blocking TNF-a shedding with an IC50 of >75 nM. Together, these studies demonstrate that the proteolytic activity of ADAM17 is differentially controlled in T and B cells and is substrate dependent.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 24 November 2022
Last Modified: 24 Nov 2022 16:32

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