Lymphatics regulation of the inflammatory clotting creates the natural on-off switch for the immune ignorance that allows subcutaneous allografting

The ability of lymph to clot indicates that, like blood vessels, lymphatics must have means to counteract this process. Here, we analyzed lymphatic hemostatic properties, tailoring them for potential therapeutic applications. Inflammatory stimuli induced tissue factor-dependent focal lymph clotting while blocking thrombomodulin leading to widespread but transient occlusion of collecting vessels. Decellularization of lymphatics resulted in tissue factor-independent lymphatic occlusion by widespread and persistent lymph clots. In occluded decellularized ghost vessels, fibrin was eventually reperfused. During the regeneration, ghost lymphatics were filled with granuloma-like clusters of antigen-presenting cells and T cells. Despite that, immune response against allografts placed under non-drained skin did not develop as long lymphatics remained occluded, the effect that could be prolonged by delaying regeneration of the decellularized collectors. When the lymph clotting was blocked, decellularized lymphatics could still drain macromolecules and leukocytes, showing that lymphatic endothelium is not necessary for the classic lymphatic functions. The control of excessive clotting emerges as the essential function of lymphatics that could explain the seeming spandrel presence of lymphatic networks in organs such as the kidney or heart, contribute to microvascular thrombosis during infection, and can be exploited to induce immune ignorance of the subcutaneous endocrine grafts.