Targeting Lymphangiogenesis After Islet Transplantation Prolongs Islet Allograft Survival

Abstract

Background Lymphatics are important for their conduit functions of transporting antigen, immune cells, and inflammatory mediators to draining lymph nodes and to the general circulation. Lymphangiogenesis is involved in many pathologic processes; however, the roles for lymphatic responses in transplantation have not been thoroughly investigated. Methods Mice were made diabetic by a single high dose of streptozotocin and then received islet allografts. Animals were treated with three different lymphatic inhibitors. FTY720, an analog of sphingosine 1-phosphate, inhibited lymphocyte migration into afferent and efferent lymphatics. Sunitinib, a kinase inhibitor, blocked several receptors, including vascular endothelial growth factor receptor 3 (VEGFR3), the major growth factor receptor for lymphatic endothelial cells. Anti-VEGFR3 monoclonal antibody specifically inhibited VEGFR3. Diabetes was determined by daily monitoring of blood glucose levels. Inflammation within islet grafts was assessed by immunohistochemistry for insulin, T cells (CD3), and lymphatics (LYVE-1). Results After transplantation, lymphangiogenesis occurred in islet allografts and in draining lymph nodes. FTY720, sunitinib, and anti-VEGFR3 each inhibited lymphangiogenesis in the islets and significantly prolonged allograft survival. Immunofluorescent staining demonstrated that administration of each of the lymphatic inhibitors resulted in preservation of islets and β-cells along with a markedly reduced infiltration of T cells into the grafts. Conclusion Lymphangiogenesis occurs in islet allografts in response to inflammation and plays a key role in the islet inflammation in alloimmunity. Interfering with lymphatic function leads to inhibition of lymphangiogenesis and prolonged or indefinite allograft survival. These observations suggest new therapeutic targets for rejection and tolerance.

Interstitial Fluid and Lymph Formation and Transport: Physiological Regulation and Roles in Inflammation and Cancer

“…On the other hand, lymphangiogenesis is also frequently seen in autoimmunityrelated chronic inflammatory disorders (483,522) and in transplant rejection (241), suggesting that lymphangiogenesis may somehow contribute to immune rejection. Blocking lymphangiogenesis before experimental corneal or islet transplantation was found to decrease graft rejection (271,526), but 1-yr follow-ups of renal transplant patients found a positive correlation between transplant function and lymphangiogenesis (442). Such apparently contradictory findings raise questions of how inflammatory lymphangiogenesis affects immune response in different types of inflammation.…”

“…In addition to cancer, lymphangiogenesis occurs in chronic inflammation and in lymph nodes draining the inflamed regions (175,207,483,522,526). Currently, very little is known about how inflammatory lymphangiogenesis affects immunity, and the literature is puzzling.…”

Inflammation-associated lymphangiogenesis: a double-edged sword?

“…Increased lymphangiogenesis promotes the migration of APCs carrying foreign tissue antigens to the recipient's draining LNs, which provokes inflammation and is assumed to facilitate the initial immune cascade events that trigger adverse immune reactions. Some studies have shown that interference with lymphatic function suppresses lymphangiogenesis and prolongs graft survival (52,83). Other studies, using an experimental corneal graft model, identified early post-transplantation lymphangiogenesis as a significant risk factor for immune rejection after keratoplasty, which can be reduced with postoperative anti-angiogenic/antilymphangiogenic treatments (84)(85)(86).…”

“…In a diabetic mouse model transplanted with pancreatic islet allografts, lymphangiogenesis occurred in the islet allografts and in draining LNs after transplantation (83). However, antilymphatic treatment using anti-VEGFR-3 antibody, FTY720, or sunitinib inhibited IAL and significantly prolonged graft survival (83).…”

“…There is a great need for strategies to modulate the recipient's immunity to promote graft survival and function while avoiding excessive immunosuppression. Afferent lymphatic vessels serve as a route for the delivery of both donor and recipient APCs, which carry allogenic tissue antigens to the regional LNs (83). Increased lymphangiogenesis promotes the migration of APCs carrying foreign tissue antigens to the recipient's draining LNs, which provokes inflammation and is assumed to facilitate the initial immune cascade events that trigger adverse immune reactions.…”