Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

J Clin Invest. 2015 Nov 2;125(11):4255-68. doi: 10.1172/JCI79693. Epub 2015 Oct 20.

Abstract

Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Allografts
  • Animals
  • Endothelial Cells / metabolism
  • Forced Expiratory Volume
  • Glycoproteins / metabolism
  • Graft Rejection / drug therapy
  • Graft Rejection / physiopathology
  • Graft Rejection / therapy*
  • Homeodomain Proteins / analysis
  • Humans
  • Hyaluronic Acid / chemistry
  • Hyaluronic Acid / metabolism*
  • Immunosuppressive Agents / therapeutic use
  • Lung / drug effects
  • Lung / metabolism
  • Lung / physiopathology
  • Lung Transplantation*
  • Lymphangiogenesis* / drug effects
  • Lymphatic Vessels / pathology
  • Lymphatic Vessels / surgery
  • Male
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Molecular Weight
  • Mutation
  • Prednisone / therapeutic use
  • Protein Binding
  • Tumor Suppressor Proteins / analysis
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / pharmacology
  • Vascular Endothelial Growth Factor C / therapeutic use*
  • Vascular Endothelial Growth Factor Receptor-3 / drug effects*
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism

Substances

  • Glycoproteins
  • Homeodomain Proteins
  • Immunosuppressive Agents
  • Membrane Transport Proteins
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor C
  • Xlkd1 protein, mouse
  • prospero-related homeobox 1 protein
  • vascular endothelial growth factor C, mouse
  • Hyaluronic Acid
  • Vascular Endothelial Growth Factor Receptor-3
  • Prednisone