title: Endothelial vulnerability and endothelial damage are associated with risk of graft-versus-host disease and response to steroid treatment.
abstract: There is accumulating evidence indicating that endothelial factors are involved in the pathogenesis of GVHD. We have recently shown that steroid-refractory, but not sensitive, GVHD is characterized by higher pretransplantation serum levels of angiopoetin-2 (ANG2), a hormone mediating endothelial vulnerability. To evaluate whether endothelial vulnerability is a risk factor for GVHD per se or becomes important only when noticeable GVHD is established, we measured ANG2 along with additional serum markers of endothelial stress, including soluble thrombomodulin (sTM), IL-8 (CXCL8), and hepatocyte growth factor (HGF), in patients with no, low-grade, or severe GVHD. Patients with refractory GVHD exhibited elevated serum levels of ANG2, sTM, HGF, and IL-8 posttransplantation compared with patients with sensitive GVHD and patients without GVHD. Pretransplantation ANG2 was the only growth factor correlated with the risk of refractoriness and mortality, and then only within the subset of patients who developed grade III-IV GVHD. In contrast, ANG2 was not predictive of GVHD or nonrelapse mortality (NRM) in patients with no GVHD or low-grade GVHD. These findings provide evidence that endothelial function plays an important role in the pathogenesis of steroid refractoriness in ongoing GVHD; however, endothelial vulnerability does not predict incidence of GVHD.
authors.affiliation: Department of Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Dietrich
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Suzan
authors.initials: S
authors.lastname: Karamustafa
authors.forename: Esther
authors.initials: E
authors.lastname: Hahn
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.forename: Ute
authors.initials: U
authors.lastname: Hegenbart
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.forename: Peter
authors.initials: P
authors.lastname: Dreger
authors.forename: Thomas
authors.initials: T
authors.lastname: Luft
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004730:Endothelium, Vascular / Q000293:injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage*; D006086:Graft vs Host Disease / Q000097:blood / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D006402:Hematologic Diseases / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D017228:Hepatocyte Growth Factor / Q000097:blood; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D015994:Incidence; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D011239:Prednisolone / Q000008:administration & dosage*; D012189:Retrospective Studies; D012307:Risk Factors; D018180:Thrombomodulin / Q000097:blood; D014184:Transplantation, Homologous; D033921:Vesicular Transport Proteins / Q000097:blood
chemical_list: C508606:CXCL8 protein, human; D005938:Glucocorticoids; C066855:HGF protein, human; D007166:Immunosuppressive Agents; D016209:Interleukin-8; C546931:THBD protein, human; D018180:Thrombomodulin; C555023:VPS51 protein, human; D033921:Vesicular Transport Proteins; D017228:Hepatocyte Growth Factor; D011239:Prednisolone; D009173:Mycophenolic Acid