(568t) Lymphatic Drainage in Immunity: Implications in Lymph Node Targeting Strategies for Immunomodulation

Engineering strategies targeting lymph nodes are increasingly explored for immunotherapeutic applications. Lymphatic vessels are responsible for the transport of interstitial fluid, soluble antigen and immune cells from peripheral tissues to the lymph nodes for surveillance by lymph node-resident leukocytes. There is increasing evidence that lymph-borne soluble antigen plays important roles in B cell immunity, but the contribution of peripheral lymphatic drainage to immunity is poorly understood. We evaluated immune responses in K14-VEGFR-3-Ig mice, which lack dermal lymphatic capillaries and have poor dermal lymphatic transport of solutes and dendritic cells from the skin. Though smaller with altered architecture, lymph nodes of K14-VEGFR-3-Ig mice contained similar fractions of leukocyte populations compared to wildtype mice. Upon dermal immunization with the model antigen ovalbumin (OVA), K14-VEGFR-3-Ig mice displayed drastically depressed anti-OVA antibody titers compared to wildtype littermates. Surprisingly, K14-VEGFR3-Ig and wildtype mice had similar frequencies of antigen-specific CD8+ T cells as well as production of IFN-g and IL-4 upon ex vivo restimulation of lymph node or splenic cells 21 days post-immunization. Finally, 1-year old K14-VEGFR-3-Ig mice showed evidence of autoimmunity, including enhanced IgG3 serum titers, increased splenic plasmacytes and elevated urine protein levels compared to age-matched wildtype mice. In conclusion, these data suggest that lymphatic drainage plays pivotal roles in regulating humoral immunity and peripheral tolerance and hold implications for the rational design of lymph node-targeting immunotherapeutics.