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Title: The role of CXCR4/SDF-1 and VLA-4/VCAM-1 in migration of bystander-activated T cells : implications for rheumatoid arthritis
Author: Bryant, Jane
ISNI:       0000 0004 2709 8394
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Bystander lymphocytes generated in vitro by cytokine stimulation (IL-2, IL-6, TNFα) have previously been shown to demonstrate significant identity in phenotype and activation of monocyte signalling pathways to T cells isolated from rheumatoid arthritis (RA) synovial tissue. Tck are a therefore relevant surrogate model for studying the RA T cell. The results presented in this thesis extend previous studies of cytokine- activated T cells (Tck) through phenotypic analysis and determination of migratory responsiveness. Cytokine stimulation upregulated expression of chemokine receptors and integrins on Tck, including CXCR4, VLA-4 and LFA-1. Results of in vitro chemotaxis and extravasation studies revealed that increased expression of CXCR4 and VLA-4 integrin resulted in concentration-dependent Tck migration to their ligands, CXCL12 and VCAM-1, which could be blocked through specific inhibitors and neutralizing antibodies. Increased expression of VLA-4 and LFA-1 also resulted in increased Tck extravasation, inhibited through blockade of VLA-1, LFA-1 or their ligands. Moreover, Tck demonstrated an increased chemotactic response to RA fibroblast- like synoviocytes cultured in vitro, which could be decreased using inhibitors against VLA-4 and CXCR4. The RA/ SCID mouse model was established to assess Tck migratory responsiveness in vivo; however the model did not prove sufficiently robust to definitively determine if the in vitro results reflected the situation in vivo. The activated phenotype of Tck results in increased migratory responsiveness to chemokines and proteins found in the RA synovial joint environment. Tcks elicit proinflammatory cytokine production from monocytes, which was further increased in the migrated Tck subset. Tck also exhibit a phenotype similar to RA synovial tissue T cells, indicating that cytokine activation of T cells could contribute to RA pathogenicity by migration and subsequent cell-cell interactions, perpetuating the inflammatory cascade in RA. The CXCR4/ CXCL12 and VLA-4/ VCAM-1 axes could also potentially be exploited for therapeutic gain in treatment of RA.
Supervisor: Brennan, Fionula Sponsor: Arthritis Research UK ; Kennedy Institute Trustees
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral