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Characterisation of the immune cells and cytokines involved in a model of atopic dermatitis

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thesis
posted on 23.11.2021, 09:51 by Naidoo, Karmella

Atopic dermatitis (AD) is a highly debilitating disease with significant health impacts worldwide. It is a chronic and relapsing inflammatory skin disease which often poses a life-long burden for the affected individuals. AD has been a difficult disease to treat as it manifests with a wide spectrum of clinical phenotypes and the current clinical management strategies are non-specific. Therefore, it is imperative to identify specific immunological pathways that could be targeted to treat this disease. Previous studies have documented that AD disease progression is precipitated by a combination of skin barrier dysfunction, itch and immune dysregulation that are responsible for AD progression. However, the precise role of effector cells and cytokines have not been fully elucidated. To address this, I established a clinically relevant model of AD, using the vitamin D analogue, MC903. This MC903 model closely resembles the AD phenotype in patients, including inflammatory parameters, barrier dysfunction, itch, and histopathological characteristics, providing a novel platform to evaluate targets for the treatment and prevention of AD. Furthermore, this model exposed the cells and cytokines that are critically associated with disease severity, including eosinophils, mast cells, TSLP, IL-4 and IL-9, but not CD4+ T cells. The instrumental role of these effector cells and cytokines was established by their stepwise depletion or blockade. Indeed, functional eosinophil depletion via the use of inducible eosinophil (iPHIL) mice significantly ameliorated AD pathology, most notably itch. Similar results were obtained after blockade of the IL-4/IL-13 axis by genetic deletion of STAT6. The clinically more relevant use of soluble inhibitors targeting IL-9 and CRTh2 (in a prophylactic and therapeutic setting, respectively), both resulted in a substantial reduction in AD phenotype. In summary, this body of work led to the identification of key disease-initiating and effector cells and molecules that represent attractive targets for the treatment of AD.

History

Copyright Date

01/01/2018

Date of Award

01/01/2018

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Immunology

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Doctoral

Degree Name

Doctor of Philosophy

Victoria University of Wellington Unit

Malaghan Institute for Medical Research

ANZSRC Type Of Activity code

970111 Expanding Knowledge in the Medical and Health Sciences

Victoria University of Wellington Item Type

Awarded Doctoral Thesis

Language

en_NZ

Victoria University of Wellington School

School of Biological Sciences

Advisors

Le Gros, Graham