White blood cells navigate through tissue by following chemical trails, but scientists do not fully understand how those trails form in the first place. The immune system depends on chemokines—signalling proteins that guide leukocytes to sites of infection or inflammation. Lymphatic endothelial cells produce these chemokines and release them into surrounding tissue, where diffusion, fluid flow, and cellular uptake combine to create spatial gradients. When those gradients are disrupted, immune cells fail to reach their targets, and the body’s defences break down. This project will build a quantitative, integrated model of chemokine gradient formation using both experiments and computer simulations. The work is fundamental science: it aims to explain a core biological process rather than deliver an immediate treatment. However, understanding how gradients are established and regulated could eventually inform vaccine design and therapies for allergy, autoimmunity, cardiovascular disease, and cancer—conditions where immune cell positioning goes wrong.
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A functioning immune system relies on carefully tuned fluid, cellular and molecular transport processes. Chemokines are secreted chemoattractants that orchestrate the migration and positioning of leukocytes, and are indispensable components of all protective and pathogenic immune and inflammatory responses. Lymphatic endothelial cells (LECs) play a prime role in chemokine production and exchange with the surrounding tissues, where a combination of diffusion, advection, binding kinetics and cellular uptake result in the generation of spatial chemokine gradients that govern leukocyte migration. If chemokine gradients are not appropriately tuned, leukocytes fail to respond and immune responses are compromised. While previous research has revealed much about chemokine function at the sub-cellular level, there is little quantitative knowledge of how physical and biological mechanisms interact to produce functional chemokine gradients in vivo, or of how the specific characteristics of those gradients affect leukocyte behaviour. We aim to develop a comprehensive quantitative knowledge base of chemokine gradient formation and regulation using integrated experimental and modelling approaches. This will provide unprecedented insight into this complex, dynamic and critically important process, and has potential impact on vaccination and on the treatment of diseases with key immune cell contributions, such as allergy, autoimmunity, cardiovascular disease, and cancer.
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