title: A Canine Model of Chronic Graft-versus-Host Disease.
abstract: In long-term survivors of allogeneic hematopoietic cell transplantation (HCT), chronic graft-versus-host disease (GVHD) is the major cause of morbidity and mortality and a major determinant of quality of life. Chronic GVHD responds poorly to current immunosuppressive drugs, and while T cell depletion may be preventive, this gain is offset by increased relapse rates. A significant impediment to progress in treating chronic GVHD has been the limitations of existing animal models. The goal of this study was to develop a reproducible comprehensive model of chronic GVHD in the dog. Ten recipient dogs received 920 cGy total body irradiation, infusion of marrow, and an infusion of buffy coat cells from a dog leukocyte antigen (DLA)-mismatched unrelated donor. Postgrafting immunosuppression consisted of methotrexate (days 1, 3, 6, 11) and cyclosporine. The duration of cyclosporine administration was limited to 80 days instead of the clinically used 180 days. This was done to contain costs, as chronic GVHD was expected to develop at earlier time points. All recipients were given ursodiol for liver protection. One dog had graft failure and 9 dogs showed stable engraftment. Eight of the 9 developed de novo chronic GVHD. Dogs progressed with clinical signs of chronic GVHD over a period of 43 to 164 (median, 88) days after discontinuation of cyclosporine. Target organs showed the spectrum of chronic GVHD manifestations that are typically seen clinically. These included lichenoid changes of the skin, fasciitis, ocular involvement (xerophthalmia), conjunctivitis, bronchiolitis obliterans, salivary gland involvement, gingivitis, esophageal involvement, and hepatic involvement. Peripheral blood lymphocyte surface antigen expression of CD28 and inducible costimulator was elevated in dogs with GHVD compared with those in normal dogs, but not significantly so. Serum levels of IL-8 and monocyte chemotactic protein-1 in GVHD-affected dogs at time of euthanasia were elevated, whereas levels of IL-15 were depressed compared with those in normal dogs. Results indicate that the canine model is well suited for future studies aimed at preventing or treating chronic GVHD.
authors.affiliation: Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington. Electronic address: sgraves@fredhutch.org.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Graves
authors.affiliation: Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rezvani
authors.affiliation: Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pathology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: George
authors.initials: G
authors.lastname: Sale
authors.affiliation: Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Diane
authors.initials: D
authors.lastname: Stone
authors.affiliation: Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Maura
authors.initials: M
authors.lastname: Parker
authors.affiliation: Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Steven
authors.initials: S
authors.lastname: Rosinski
authors.affiliation: Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Michele
authors.initials: M
authors.lastname: Spector
authors.affiliation: Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Bruce
authors.initials: B
authors.lastname: Swearingen
authors.affiliation: Hematology-Oncology, Seattle Children's Hospital, Seattle, Washington.
authors.forename: Leslie
authors.initials: L
authors.lastname: Kean
authors.affiliation: Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, Division of Oncology, University of Washington, Seattle, Washington.
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
mesh_terms: D000818:Animals; D058621:Blood Buffy Coat / Q000637:transplantation; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000379:methods; D002908:Chronic Disease; D004195:Disease Models, Animal; D004285:Dogs; D006085:Graft Survival; D006086:Graft vs Host Disease; D006648:Histocompatibility; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008212:Lymphocyte Depletion; D019172:Transplantation Conditioning / Q000379:methods; D014181:Transplantation Immunology; D014184:Transplantation, Homologous; D061349:Unrelated Donors; D014916:Whole-Body Irradiation
chemical_list: D007166:Immunosuppressive Agents
keywords: Canine model; Chronic graft-versus-host disease