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Title: Investigation of the signal transduction pathways involved in the induction of T-lymphocyte motility
Author: Dixon, Richard
ISNI:       0000 0001 3426 1442
Awarding Body: Open University
Current Institution: Open University
Date of Award: 1996
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Induction of lymphocyte motility is an essential early step in extravasation of lymphocytes into inflammatory sites and also into lymphoid tissues in the process of lymphocyte recirculation. Lymphocyte motihty requires a change from a spherical morphology to a constantly changing irregular shape. In this study, a variety of agents have been investigated for induction of this shape changing morphology in freshly isolated human peripheral blood T-lymphocytes (PBTLs) and a non-motile variant of the MOLT-4 human lymphoid cell line. The MOLT-4 cells proved to be non-responsive to most of the agents tested, however, 5 agents were found to cause significant polarisation in PBTLs. IL-2, IL-15, fetal calf serum (PCS) and nocadazole induce shape change in 20-40% of PBTLs. However, the most potent inducer of shape change found were the PKC inhibitors of the bisindolylmaleimide (Bis) type, which show effects on over 60% of PBTLs, as reported recently. Do these diverse inducers of shape changing in PBTLs act by a common signal transduction pathway? With IL-2, IL-15, PCS, nocadazole and Bis., no common changes in intracellular calcium flux, intracellular pH, inositol triphosphate levels, renaturable kinase activity and tyrosine phosphorylation have been found. So if a final common signaltransduction pathway exists, it must involve other second messenger systems. However, a number of pharmacological agents were found to prevent the induction of shape change in PBTLs, indicating that they could be targeting a common second messenger element involved in motility signal transduction. Comparisons of their chemical structures revealed no common structural motifs that would explain their common effects on lymphocyte motility.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Biochemistry