Harnessing the potential of mRNA vaccination as a therapeutic strategy for asthma

Objective

Dendritic cells (DCs) are antigen presenting cells that promote immunity to pathogens, as well as tolerance to innocuous antigens, and are therefore critical regulators of both immunity and immune homeostasis. However, during asthma this ability to promote peripheral tolerance is dysregulated, leading to the formation of inappropriate TH2 responses to harmless antigens, and allergic inflammation in the airway. Peripheral tolerance has been postulated to be promoted by DCs undergoing homeostatic maturation, a process by which DCs become activated, migrate, and gain the ability to present antigen in the absence of inflammatory stimuli. Recent data from my host laboratory has shown that DCs exposed to unadjuvanted lipid nanoparticles (LNP) undergo homeostatic maturation, mimicking the response DCs mount to apoptotic bodies. In addition, unadjuvanted LNPs containing peptide cargo lead to reduced T cell responses mounted to these specific peptides, suggesting that LNPs can promote peripheral tolerance. LNP vaccines containing purified mRNA free of dsRNA contaminants also can be rendered non-immunogenic. mRNAsthma aims to adapt this phenomenon to the lung tissue microenvironment, by which DC and T cell responses to mRNA vaccines will be characterised at steady-state and during airway inflammation. In a subsequent step, we will assess if we can exploit this approach to protect from HDM-induced asthma. mRNAsthma also has an ambitious CITEseq experiment, to generate mechanistic insight of the interactions between cDC and T cells in the lung. mRNAsthma represents an important step in my research career, to increase my skillset and learn from leaders in my field. I will use this project to advance my skills in bioinformatic analysis, as well as my skills in leadership, mentorship and science communication. mRNAsthma is therefore an ambitious project of significant translational potential, with mechanistic understanding of tolerance by cDCs central to its success.