A Canine Model of Chronic Graft-Vs.-Host Disease.

Publication Type:

Journal Article

Source:

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Volume 23, Issue 3, p.420-427 (2017)

Keywords:

Comparative Medicine Core Facility

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 preventative, 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 in order to contain costs since chronic GVHD was expected to develop at earlier time points. All recipients were given ursodiol for liver protection. One dog had graft failure while 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 ICOS was elevated in dogs with GHVD compared to normal dogs but not significantly so. Serum levels of IL-8 and MCP-1 in GVHD affected dogs at time of euthanasia were elevated, while levels of IL-15 were depressed compared to normal dogs. Results indicate that the canine model is well suited for future studies aimed at preventing or treating chronic GVHD.