Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival

Transplantation. 2011 Jul 15;92(1):25-30. doi: 10.1097/TP.0b013e31821d2661.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Diabetes Mellitus, Experimental / surgery
  • Fingolimod Hydrochloride
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control
  • Graft Survival / drug effects
  • Graft Survival / immunology*
  • Immunosuppressive Agents / pharmacology
  • Indoles / pharmacology
  • Islets of Langerhans Transplantation / immunology*
  • Islets of Langerhans Transplantation / pathology
  • Lymphangiogenesis / drug effects
  • Lymphangiogenesis / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Propylene Glycols / pharmacology
  • Pyrroles / pharmacology
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Sunitinib
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Transplantation Tolerance / drug effects
  • Transplantation Tolerance / immunology
  • Transplantation, Homologous
  • Vascular Endothelial Growth Factor Receptor-3 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-3 / immunology


  • Antibodies, Monoclonal
  • Immunosuppressive Agents
  • Indoles
  • Propylene Glycols
  • Pyrroles
  • Vascular Endothelial Growth Factor Receptor-3
  • Fingolimod Hydrochloride
  • Sphingosine
  • Sunitinib