title: A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model.
abstract: BACKGROUND
  Acute graft-versus-host disease (aGVHD) poses a major limitation for broader therapeutic application of allogeneic hematopoietic cell transplantation (allo-HCT). Early diagnosis of aGVHD remains difficult and is based on clinical symptoms and histopathological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestation. Therefore, for improved disease prevention it is important to develop predictive assays to identify patients at risk of developing aGVHD. Here we address whether insights into the timing of the aGVHD initiation and effector phases could allow for the detection of migrating alloreactive T cells before clinical aGVHD onset to permit for efficient therapeutic intervention.
  
  
  METHODS
  Murine major histocompatibility complex (MHC) mismatched and minor histocompatibility antigen (miHAg) mismatched allo-HCT models were employed to assess the spatiotemporal distribution of donor T cells with flow cytometry and in vivo bioluminescence imaging (BLI). Daily flow cytometry analysis of peripheral blood mononuclear cells allowed us to identify migrating alloreactive T cells based on homing receptor expression profiles.
  
  
  RESULTS
  We identified a time period of 2 weeks of massive alloreactive donor T cell migration in the blood after miHAg mismatch allo-HCT before clinical aGVHD symptoms appeared. Alloreactive T cells upregulated α4β7 integrin and P-selectin ligand during this migration phase. Consequently, targeted preemptive treatment with rapamycin, starting at the earliest detection time of alloreactive donor T cells in the peripheral blood, prevented lethal aGVHD.
  
  
  CONCLUSIONS
  Based on this data we propose a critical time frame prior to the onset of aGVHD symptoms to identify alloreactive T cells in the peripheral blood for timely and effective therapeutic intervention.
authors.affiliation: Department of Medicine II, Würzburg University Clinics, Zinklesweg 10, Würzburg, D-97078, Germany.
authors.forename: Carina A
authors.initials: CA
authors.lastname: Bäuerlein
authors.forename: Simone S
authors.initials: SS
authors.lastname: Riedel
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.forename: Christian
authors.initials: C
authors.lastname: Brede
authors.forename: Ana-Laura Jordán
authors.initials: AL
authors.lastname: Garrote
authors.forename: Martin
authors.initials: M
authors.lastname: Chopra
authors.forename: Miriam
authors.initials: M
authors.lastname: Ritz
authors.forename: Georg F
authors.initials: GF
authors.lastname: Beilhack
authors.forename: Stephan
authors.initials: S
authors.lastname: Schulz
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.forename: Paul G
authors.initials: PG
authors.lastname: Schlegel
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
mesh_terms: D000208:Acute Disease; D000818:Animals; D001787:Blood Group Incompatibility / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005544:Forecasting; D006086:Graft vs Host Disease / Q000175:diagnosis* / Q000276:immunology / Q000601:surgery*; D006680:HLA Antigens / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation*; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D006680:HLA Antigens