Authors

J Furlong-Silva¹; S D Cross¹; N Pionnier¹; A Steven¹; J Archer¹; M Taylor¹; J Turner¹;  ¹ Liverpool School of Tropical Medicine

Discussion

Lymphatic Filariasis (LF) related morbidity (lymphoedema and elephantiasis) affects 40 million patients globally, making it the third leading cause of global disability by the WHO. Current treatment is limited to symptom management, suggesting novel therapies to prevent, or reverse pathology are urgently required. LF is associated with significant lymphatic remodelling and dysfunction, however the underlying mechanisms that mediate these changes, and how they relate to LF pathology is poorly understood. An LF leg pathology model was developed were 100 B. malayi L3 larvae were subcutaneously injected into the feet of mice (BALB/c and C57BL/6). An intravital imaging system was utilised to analyse lymphatic flow 2-5 weeks post infection (P.I). Intracellular cytokine staining was undertaken on lymph nodes (LNs) proximal to infection and plasma taken for luminex analysis.  Early, significant lymphatic remodelling with dilation, collateral tortuous lymphatics and dermal back flow was observed 2 weeks P.I. and was concomitant with significant expansion of IL-4/IL-13 expressing CD4 T-cells in draining LNs. Deficiencies in T/B cells or IL-4/IL13 responses- using SCID and IL-4rα KO mice- resulted in amelioration of remodelling, with a reduced incidence and magnitude in SCID vs WT mice and no significant differences between sham vs infected IL-4rα KO mice. Plasma analysis indicated significant increases in several circulating lymphangiogenic markers following infection including: VEGF-C, β-cellulin, prolactin and sALK-1. The data suggests a key role for a Th2 adaptive immune response in early lymphatic remodelling following filarial infection, with early pathological alterations associated with elevated multifactorial lymphangiogenic mediators. Together, these data reveal a Th2 lymphangiogenic pathway in the initiation of filarial lymphatic disease. Targeting this pathway may yield novel therapeutic strategies against LF pathology.