Whole-body models of human and murine lymphatic drainage basins to assess antigen and fluid transport

Introduction: The resection of sentinel lymph nodes after tumor removal is known to affect lymphedema and may alter the outcomes of immunotherapy by rerouting tumor antigen to more distant lymph nodes. In this study, we present 3D computational models of the human and murine lymphatic systems along with experiments performed in mice, with a focus on mapping fluid movement between dermal lymphatic drainage basins (lymphosomes).

Materials and

Methods: In the computational models, interstitial fluid originates from semipermeable blood capillaries, is absorbed into a superficial network of initial lymph vessels, and is ultimately collected into a deep lymphatic vasculature that includes 272 lymph nodes in humans and 42 lymph nodes in mice. By computationally disabling lymph nodes that drain specific domains of the skin, we can calculate the rate at which fluid moves through compensatory pathways to more distant lymphosomes. By dimensional analysis we have identified parameter groups that determine the extent of fluid redistribution based on vascular and tissue permeabilities and lymphatic pumping rates. The model has been validated with analytical results based on simplified geometries and by comparison to literature results of tracer imaging in patients. Our computational studies are also supported by imaging experiments in mice with surgically disabled nodes where antigen transport was simulated by 2M FITC Dextran.

Results, Conclusions, and Discussions: Our computational models demonstrate that antigen and interstitial fluid can be rerouted from a disabled lymphosome to distant sites, potentially on the opposite side of the midline (Fig. 1). While the computational results in the mouse and human models are qualitatively similar, important differences exist. For example, the direct connection from the inguinal region to the axillary region that is present in the mouse is absent in the human. Moreover, our parametric study shows that the size difference between species results in much higher interstitial pressures in humans than mice when similar regions are disabled – perhaps explaining the difficulty in developing murine models of lymphedema. However, disabling a single lymph node in the human network can have less effect than in a mouse due to the greater network redundancy in humans.

The clinical decision to resect the tumor-draining lymph nodes is often driven by the desire to limit metastasis, but this goal must be weighed against the possible adverse effects of removing these nodes. Our present results suggest that rerouting and redundancy of antigen transport within the lymphatic system may offset some of the effects immunological effects of lymph node resection, but may still result in elevated interstitial pressures and edema.

Acknowledgements (Optional): The authors gratefully acknowledge the support of NIH R01CA284601.