Peptide immunotherapy in models of allergic airways disease

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.