Modifying the lung microenvironment through gene delivery of immunomodulatory cytokines

Abstract

Respiratory infections are a leading cause of death globally, caused by various pathogens, including viruses, bacteria, and fungi. While each infection interacts differently with the immune system, all have the potential to lead to immunopathology. Immunopathology is characterised by intense inflammation, including overproduction of cytokines, reactive oxygen species, and significant infiltration of immune cells to the injury site. In some patients, this heightened immune response can cause substantial lung damage. Understanding how to control these immune responses and restore the damaged tissue remains an understudied area. In this thesis, I investigated the use of immunomodulatory cytokines with anti-inflammatory properties to modulate lung microenvironment. Through the novel genetic tools l have generated, such as the inducible transgenic mouse and the gene delivery system using adeno-associated vectors, I have target delivered cytokines to the lung environment. The approach addressed challenges associated with systemic toxicity and the short half-life of cytokines in traditional delivery systems. Specifically, I focused on delivering Interleukin 2 (IL2), Interleukin 10 (IL10), and Interleukin-1 receptor antagonist (IL1ra) to the lung and evaluated their impact on respiratory disease models including acute lung injuries caused by influenza and lipopolysaccharides (LPS), as well as chronic lung diseases like COPD. The system is elegant and efficient as it targets the lung micro-environment without impacting the other organs, allowing us to modulate and regulate the lung during an infection effectively. Next, I extended this work by proposing a synergistic approach of combining cytokines to regulate immune responses in a co-infection model of influenza-associated pulmonary aspergillosis. This condition commonly affects immunocompromised individuals. I discovered that IL2 and a triple combination of IL10, IL1ra, and IL2 could decrease neutrophilic responses during co-infection, thereby reducing the severity of the disease. These findings emphasise the essential role of a synergistic approach in providing a holistic and comprehensive treatment for respiratory infections. Overall, this thesis introduces a novel and elegant genetic tool that is cost-effective for delivering biologics to the lung, illuminating the way for treating respiratory conditions. My exploration of using IL2, IL10, and IL1ra has provided valuable insights and holds immense promise for therapeutic applications.