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.

Intestinal Lymphatic Endothelial Cells Produce R-Spondin3

“…Indeed, R-Spo3 neutralization and to a much lesser extent R-Spo2 neutralization after intestinal injury impaired tissue regeneration, indicating the critical role of intrinsic R-Spo3 production in the homeostasis of gut tissues 10 . However, our results are in sharp contrast to a recent report showing that lymphatic vessels were increased in the intestine in GVHD and that inhibition of lymphangiogenesis ameliorated murine GVHD 28 . We enumerated LECs by flow cytometry, while the previous study used histological analysis in combination with immunohistochemistry of Lyve-1.…”

Effect of High VEGF-C mRNA Expression on Achievement of Complete Remission in Adult Acute Myeloid Leukemia

“…Recent studies have shown the therapeutic efficacy of blocking lymphangiogenesis to attenuate allogeneic immune responses. Prolonged allograft survival in experimental models of islet, tracheal, cardiac, and corneal transplantation has been reported [38] , [39] , [40] , [41] , [42] , [43] , and in addition, anti-FLT4 antibody ameliorated aGVHD and improved survival in murine models [44] . Our data demonstrated that VEGF-C expression was related to CR achievement after induction chemotherapy and changes in immune cell frequency according to VEGF-C mRNA expression in humans.…”

Endothelial damage and dysfunction in acute graft-versus-host disease

“…aGVHD models were used as described previously. [2][3][4] For chemotherapy based models, 7 days before bone marrow transplantation (BMT), female B6 or BDF mice received 20mg/kg/day busulfan (Sigma Aldrich, USA) i.p. on 5 consecutive days.…”

“…However, the 20%-25% of patients who fail initial treatment with steroids (steroid-refractory aGVHD [SR-aGVHD]) have very high mortality. 2,3 No standard treatment for SR-aGVHD is currently available, and its pathobiology is poorly understood, thereby hindering the development of novel therapeutic approaches.…”