Anti-clotting functions of lymphatics form the natural on-off switch for immune recognition by controlling the antigens and immune cells access to the lymph nodes

Abstract

The ability of lymph to clot indicates that similar to blood vessels lymphatics must have means to counteract this process. We analyzed their hemostatic properties, tailoring them for the potential therapeutic applications. Inflammatory stimuli induced tissue factor-dependent focal lymph clotting while blocking thrombomodulin lead to widespread but also transient occlusion of collecting vessels. Decellularization of lymphatics resulted in tissue factor-independent lymphatic occlusion by widespread and persistent lymph clots. These decellularized basement membrane remnants of collectors were capable of macromolecules drainage and leukocytes transit only when lymph clotting was inhibited with heparin. In occluded ‘ghost’ vessels, fibrin was replaced with transient basement membrane-rich inclusions to be eventually reperfused. During regeneration, ghost vessels were filled with granuloma-like clusters of antigen-presenting and T cells. Despite that, immune response against allografts placed under non-drained skin was not developed as long lymphatics remained occluded, and graft survival was prolonged together with the delay of lymphatic regeneration with anti-lymphangiogenic therapy. Other potential applications of lymphatic hemostatic control functions include blocking pathogen or metastasis spread but also should be considered in the treatment of lymphedema.