Using genomic approaches to characterise the immune response to biologicals

Abstract

Biologic therapies are effective treatments for inflammatory bowel disease (IBD). Successful treatment leads to reduced hospitalisation and surgeries, and an improvement in quality of life for patients. Unfortunately, the use of these treatments are associated with challenges such as treatment failure, an increased risk of infections, and suboptimal vaccine responses. An understanding of the molecular mechanisms underlying the challenges of existing IBD therapies, such as anti-tumour necrosis factor (anti-TNF), will allow strategies to be developed to overcome these challenges and aid drug sequencing. Technological advances in genomics has enabled a deeper understanding of these molecular mechanisms.

The primary aim of this thesis was to utilise genomic approaches to understand the molecular mechanisms underlying the effects of anti-TNF therapies in the setting of treatment failure and attenuated vaccine response. In this thesis, I demonstrated that DNA methylation profiles might potentially be used as a predictor for anti-TNF drug concentration at week 14, which is the only modifiable factor associated with primary non-response to anti-TNF at week 14. In the setting of the COVID-19 pandemic, I demonstrated that antibody response following SARS-CoV-2 vaccine was attenuated in patients treated with infliximab compared to vedolizumab. Using genomic approaches including DNA methylation and single-cell RNA profiling, I identified acute but non-persistent changes in immune cell proportions following a third dose of SARS-CoV-2 vaccine, and identified baseline DNA methylation signatures that were associated with vaccine antibody response. Further, I optimised a pipeline for profiling single cell gene expression in human PBMC samples from an observational cohort study.

The findings from my thesis have improved understanding of the molecular mechanisms underlying the challenges of IBD therapies using genomic approaches. Overall, it has changed clinical practice, influenced government policies, and brings us one step closer to implementing personalised treatments for patients with IBD.