title: Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system.
abstract: Acute graft-versus-host disease (GVHD) is a major complication of allogeneic stem cell transplantation (SCT) and can be readily controlled by systemic high-dose steroids in many patients. However, patients whose GVHD is refractory to this therapy have a poor prognosis. Refractory patients have ongoing end-organ damage despite effective immunosuppression with second-line regimens, suggesting pathomechanisms independent from the initiating T-cell attack. To explore whether endothelial damage might contribute to GVHD refractoriness and to study the role of angiopoietin-2 (ANG2) in this process, we have compared kinetics of T-cell activation markers and markers of endothelial dysfunction in the serum of patients with sensitive (n = 23) and refractory GVHD (n = 25). Longitudinal measurements of soluble FAS ligand along with other immune markers demonstrate that refractory patients are not exposed to an overwhelming or unresponsive T-cell attack. However, in contrast to sensitive GVHD, refractory GVHD was associated with rising thrombomodulin levels and high ANG2/ vascular endothelial-derived growth factor ratios. Patients with refractory GVHD showed significantly increased ANG2 levels already before SCT. These results suggest that endothelial cell vulnerability and dysfunction, rather than refractory T-cell activity, drives treatment refractoriness of GVHD and opens new avenues for prediction and control of this devastating condition.
authors.affiliation: Department of Medicine V, University of Heidelberg, Heidelberg, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Luft
authors.forename: Sascha
authors.initials: S
authors.lastname: Dietrich
authors.forename: Christine
authors.initials: C
authors.lastname: Falk
authors.forename: Michael
authors.initials: M
authors.lastname: Conzelmann
authors.forename: Michael
authors.initials: M
authors.lastname: Hess
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Frank
authors.initials: F
authors.lastname: Neumann
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
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
mesh_terms: D000328:Adult; D042702:Angiopoietin-2 / Q000097:blood / Q000276:immunology; D000075906:Chemokine CCL26; D054428:Chemokine CX3CL1 / Q000097:blood / Q000276:immunology; D054365:Chemokine CXCL5 / Q000097:blood / Q000276:immunology; D019742:Chemokines, CC / Q000097:blood / Q000276:immunology; D004351:Drug Resistance; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000097:blood / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D013256:Steroids / Q000276:immunology / Q000627:therapeutic use*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000097:blood / Q000276:immunology; D018180:Thrombomodulin / Q000097:blood / Q000276:immunology; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000276:immunology; D055815:Young Adult
chemical_list: D042702:Angiopoietin-2; C120429:CCL26 protein, human; D000075906:Chemokine CCL26; D054428:Chemokine CX3CL1; D054365:Chemokine CXCL5; D019742:Chemokines, CC; D053222:Fas Ligand Protein; D013256:Steroids; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D018180:Thrombomodulin; D042461:Vascular Endothelial Growth Factor A