Targeting Lymphangiogenesis After Islet Transplantation Prolongs Islet Allograft Survival

The encounter of antigen-presenting cells (APCs) and T cells in secondary lymphoid organs is essential for the initiation of immune responses, so that interfering with leukocyte trafficking could modulate immunity. Lymphatics are important for their immunologic conduit functions of transporting antigen, immune cells, and inflammatory mediators from tissues to draining lymph nodes (LNs), and from secondary lymphoid organs to the general circulation (1–4). Lymphatics are also found within LN (5) and are important for intranodal leukocyte migration, along with modulating the expression and production of chemokines and other immune mediators (3, 4). Lymphatics undergo growth and remodeling during immunity (3, 4, 6); and lymphangiogenesis is present in many pathologic processes (1, 2, 7, 8). Human and rodent corneal transplantation induces new lymphatic vessels in the corneal graft bed. These vessels facilitate delivery of APCs to draining and systemic LNs to enhance immune responses (9, 10) and play an active role in corneal transplant rejection (10). In contrast, stimulation of lymphangiogenesis inhibits chronic skin inflammation (11). Therefore, the roles of lymphatics in regulating immune responses and how lymphatics are regulated are unclear. A functional lymphatic network is found in transplanted syngeneic islets (12). However, the significance of islet lymphatic vessels and lymphangiogenesis and their contribution to immunity are incompletely understood. Vascular endothelial growth factors (VEGFs) C and D, and their receptor VEGFR3, are the most potent mediators of lymphatic growth (13–15). Lymphangiogenesis and lymphatic metastasis can be efficiently inhibited by VEGF C/D trap, neutralizing anti-VEGFR3 antibodies (13–15), or small molecule tyrosine kinase inhibitors that down-regulate VEGFR signaling, such as sunitinib (16). We took advantage of this knowledge and these reagents to explore the roles of lymphangiogenesis in islet allotransplantation. Lymphangio-genesis occurred both in islet allografts and the downstream draining LNs. The mechanistically diverse inhibitors of lymphatics such as FTY720, sunitinib, and anti-VEGFR3 monoclonal antibodies (mAbs) decreased graft or LN lymphangiogenesis, decreased T-cell infiltration into grafts, preserved islet architecture and function, and delayed or prevented rejection. These results show that lymphatics are not only simply conduits for cells and molecules but also active participants in inflammation and rejection, and targeting them is a powerful means to inhibit immunity.