Computational modelling and experimental evaluation of fluid and mass transport in lymph node with implications in inflammation

Abstract

The lymphatic system plays a critical role in normal physiology and is associated with pathologies from lymphoedema to cancer metastasis. A primary role of the lymphatic system is to transport lymph containing pathogens and immune cells from tissues to lymph nodes (LNs) where humoral and cellular adaptive immune response is initiated. Despite the importance of fluid and proteins transport to specific regions of the LN in proper immune response, little is known about fluid distribution and its modulation under different pathologic conditions such as inflammation. Four studies in this thesis set out to improve our understanding of how lymph transport in the LN modulates its function. The first study established a computational model of fluid flow in the LN demonstrating its important role in fluid exchange with blood vessels, and determined medulla hydraulic conductivity as the key parameter for controlling hydraulic resistance of the LN. In the second study, the experimentally measured LN resistance showed an increase after inflammation, which was associated with medulla hydraulic conductivity. The third study demonstrated an application of this model in providing insight into the role of lymph transport in formation of interfollicular chemokine gradients in the LN that are crucial for antigen presenting cell entry to LN paracortex. In the fourth study, the effect of shear stress that is present in the sinuses of the LN was examined on the calcium dynamics of the lymphatic endothelium. Overall, this research revealed that lymph flow both modulates (e.g. chemokine gradient formation and calcium signalling) and is modulated by (e.g. hydraulic resistance change with inflammation) LN function. The lymph flow plays a critical role in fluid balance and immune response and has a great potential as a therapeutic target for modulating immune response.