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Title: Dendritic cell maturation, migration and function
Author: Suri, Rakesh Mark
ISNI:       0000 0001 3491 3332
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 1998
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Dendritic cells (DC) have a fundamental role in priming naive T-cell responses and a suspected importance in the regulation of central and peripheral tolerance. Before DC can be responsibly used in human clinical trials, the generation of both immature and mature subsets must be standardised and their in vivo migratory and functional characteristics explored. The generation of human blood monocyte-derived DC in either fetal calf serum (PCS) or autologous plasma (HP) were compared. Phenotypic and functional assays demonstrated that DC derived from either system were similarly immature and underwent comparable maturation in response to LPS, TNF-α and MCM (decreasing potencies.) Furthermore, we demonstrated that adherent cells from HP cultures were likely DC but failed to react with the anti-rat CD8 antibody OX-8 which labels nonadherent DC. DC grown from mouse bone marrow (BMDC) using GM-CSF (GM) plus (IL4) were capable of undergoing further maturation with TNF-α or LPS. In contrast, the growth of BMDC in GM alone, gave rise to N418+ immature DC which could not be matured subsequently using TNF-α, LPS or IL1-β under our conditions. The migration of immature and mature BMDC was compared after IV injection. Fluorochrome labelled cells were found in splenic T-cell areas 24 hours after injection of all DC subsets into either syngeneic or allogeneic hosts. Furthermore, DC could be re-isolated from spleen and characterised by FACS analysis at various times after administration. Tc-99m radiolabel studies demonstrated similar quantitative migration of BMDC subsets and primary splenic DC (LODACS) to peripheral tissues (spleen, liver and lung) by 24 hours after injection. Emerging evidence suggests that inhibition of costimulatory signalling during antigen presentation may lead to specific unresponsiveness. The ability of immature versus mature donor strain DC pre-treatment to alter cardiac allograft survival was investigated. Only GM-DC (immature) but not more mature GM/IL4-DC subsets were capable of inducing significant graft survival prolongation (MST>100d). Furthermore, the effect was dependant upon pre-treatment 7d before transplantation and was strain specific. The CD4+ T-cell priming patterns of immature versus mature BMDC were investigated using TCR transgenic mice recognising OVA plus MHCII. Mature OVApulsed DC were able to induce antigen-specific T-cell proliferation, activation marker upregulation and intracellular IL2, IL4 and TNF-α production, while immature GMDC proliferation was less, activation marker expression limited, and no IL4 seen. Our findings represent the first demonstration that cytokine cultured DC migrate similarly to primary DC after IV injection. Furthermore, the comparable migratory patterns of immature and mature BMDC subsets contrasts with differences in CD4+ T-cell priming responses in spleen and the unique ability of immature GM-DC to selectively induce cardiac allograft prolongation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Genetics