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Title: The regulation of lung homeostasis and influenza-associated inflammation
Author: Lyonga, Daphne E.
ISNI:       0000 0004 2709 9346
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Alveolar macrophages are the main cell population in the naïve airway and are held in a state of tight regulation by several suppressive mechanisms. One would expect them to display a regulatory phenotype but here we show that at homeostasis they express markers of alternative activation such as YM1 and mannose receptor (MR) but not resistin-like molecule (RELM)-α. We show also that these markers are differentially regulated during influenza infection on macrophage populations in the lungs and airways. We hypothesised that removing the suppressive effects of IL-10 using an IL-10R blocking antibody would alter alveolar macrophage phenotype and the immune response to influenza infection. We now demonstrate that IL-10R blockade does not significantly alter the phenotype of alveolar macrophages at homeostasis but does increase in their numbers and infiltrate of monocyte/macrophages and T cells into the airways during a subsequent influenza infection. Blockade of the interaction between the co-stimulatory molecule GITR and its ligand GITRL is beneficial for disease outcome in mouse models of chronic lung inflammation; therefore we hypothesised that it may also abrogate influenza-associated immune pathology. We now show that GITR and GITRL are differentially expressed in the lungs and airways during influenza infection; however contrary to expectations, blockade of the interaction between the two accelerated influenza-induced weight loss and lung cellularity. This may indicate a novel regulatory role for GITRL in influenza-induced inflammation. This thesis shows that alveolar macrophages represent an atypical alternatively activated macrophage population, whose phenotype is not altered by IL-10R blockade. However, we show that prior IL-10R blockade can alter the immune response to subsequent influenza infection, and blockade of GITRL during influenza infection may be detrimental for the outcome of influenza infection.
Supervisor: Hussell, Tracy ; Wissinger, Erika Sponsor: NIH
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral