title: Lymphangiogenesis is a feature of acute GVHD, and VEGFR-3 inhibition protects against experimental GVHD.
abstract: Lymph vessels play a crucial role in immune reactions in health and disease. In oncology the inhibition of lymphangiogenesis is an established therapeutic concept for reducing metastatic spreading of tumor cells. During allogeneic tissue transplantation, the inhibition of lymphangiogenesis has been successfully used to attenuate graft rejection. Despite its critical importance for tumor growth, alloimmune responses, and inflammation, the role of lymphangiogenesis has not been investigated during allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that acute graft-versus-host disease (aGVHD) is associated with lymphangiogenesis in murine allo-HSCT models as well as in patient intestinal biopsies. Inhibition of aGVHD-associated lymphangiogenesis by monoclonal antibodies against vascular endothelial growth factor receptor 3 (VEGFR-3) ameliorated aGVHD and improved survival in murine models. The administration of anti-VEGFR-3 antibodies did not interfere with hematopoietic engraftment and improved immune reconstitution in allo-HSCT recipients with aGVHD. Anti-VEGFR-3 therapy had no significant impact on growth of malignant lymphoma after allo-HSCT. We conclude that aGVHD is associated with lymphangiogenesis in intestinal lesions and in lymph nodes. Our data show that anti-VEGFR-3 treatment ameliorates lethal aGVHD and identifies the lymphatic vasculature as a novel therapeutic target in the setting of allo-HSCT.
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mertlitz
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, and.
authors.forename: Martina
authors.initials: M
authors.lastname: Kalupa
authors.affiliation: Department of Hepatology and Gastroenterology and Molecular Cancer Research Center, Tumor Targeting Laboratory, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany; and.
authors.forename: Carsten
authors.initials: C
authors.lastname: Grötzinger
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, and.
authors.forename: Jörg
authors.initials: J
authors.lastname: Mengwasser
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, and.
authors.forename: Katarina
authors.initials: K
authors.lastname: Riesner
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, and.
authors.forename: Steffen
authors.initials: S
authors.lastname: Cordes
authors.affiliation: Institute for Pathology, Charité University Medicine, Campus Mitte, Berlin, Germany.
authors.forename: Sefer
authors.initials: S
authors.lastname: Elezkurtaj
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, and.
authors.forename: Olaf
authors.initials: O
authors.lastname: Penack
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007410:Intestinal Diseases; D008198:Lymph Nodes / Q000473:pathology; D042583:Lymphangiogenesis; D051379:Mice; D014184:Transplantation, Homologous; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D040321:Vascular Endothelial Growth Factor Receptor-3