Peptide immunotherapy in models of allergic airways disease
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Date
25/11/2011Author
MacKenzie, Karen Joan
Metadata
Abstract
Allergen-reactive CD4+ T cells are implicated in the pathogenesis of allergic disease.
Peptide immunotherapy (PIT) involves therapeutic administration of short
immunodominant peptides from within the protein allergen to which CD4+ T cell
responses are directed. This approach can induce tolerance of allergen-reactive CD4+
T cells, while negating the risk of severe allergic reactions associated with whole
allergen specific immunotherapy. PIT therefore holds promise as a diseasemodifying
treatment for allergic patients. However, further information regarding the
mechanisms of action of PIT are required to aid translation to the allergy clinic.
Chicken ovalbumin (OVA) is a commonly used model allergen in mouse models of
allergic airways inflammation (AAI). Trackable, T cell receptor transgenic T cells
recognizing the immunodominant 323-339 peptide of OVA (pOVA) allow
mechanistic investigation of PIT in response to pOVA. This thesis investigated the
hypothesis that strong, systemic T cell responses induced by intravenous
administration of soluble pOVA will induce i) tolerance to pOVA and ii) linked
suppression to any additional OVA T cell epitopes, hence improving OVA-induced
AAI. Contrary to the hypothesis, intravenous pOVA PIT did not improve disease in a
C57BL/6 model of OVA-induced AAI. Models of OVA-induced allergic
sensitisation and AAI were therefore developed incorporating trackable CD4+
pOVA-reactive T cells (OT-II cells). pOVA PIT induced tolerance of these cells in
an allergic sensitisation setting, but had limited impact on the overall OVA response.
Yet, in a model of AAI driven solely by Th2 polarised CD4+ OT-II cells, pOVA PIT
did improve disease. It was concluded that, in non-transgenic C57BL/6 mice, CD4+
T cells responding to additional epitope(s) within OVA were important in driving
disease and that these T cells were not subject to linked suppression following pOVA
PIT. Using a panel of overlapping peptides constituting the sequence of OVA, a
novel CD4+ epitope within OVA was characterised. The effects of PIT using pOVA
in combination with a peptide containing this additional epitope on OVA-induced
AAI were then assessed. Findings from this project therefore hold importance for
future mechanistic work surrounding PIT in allergic disease.