Anti-ICOS mAb Targets Pathogenic IL-17A-expressing Cells in Canine Model of Chronic GVHD

Abstract

Background: Chronic graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality in transplant patients. We have previously shown that 3 doses of an anti-ICOS mAb transiently ameliorated symptoms and extended survival of dogs affected by chronic GVHD over that of control dogs. The purpose of this study was to specifically correlate changes in T-cell populations in the peripheral blood with anti-ICOS treatment and chronic GVHD progression and regression in order to reach a better understanding of the mechanism of the disease and prioritize future studies. Methods: Peripheral blood cells from canines transplanted with DLA-mismatched bone marrow and PBMC to generate chronic GVHD were analyzed by flow cytometry using a panel of antibodies specific to helper and cytolytic T cells. Results: Chronic GVHD was specifically associated with an increase in CD4⁺ICOS⁺ cells, ICOS⁺ cells expressing IL-17A, and CD8⁺ cells generating granzyme B. Treatment with anti-ICOS mAb at onset of chronic GVHD symptoms specifically targeted IL-17A⁺-expressing cells, transiently relieved symptoms, and lengthened survival but was unable to reduce the percentage of CD8⁺ T-cells expressing granzyme B. Conclusions: These studies suggested a role for both CD4⁺ and CD8⁺ T cells in pathogenesis of chronic GVHD in the canine model. We propose that future studies should focus on further extending survival by developing a treatment that would control both CD4⁺ and CD8⁺ T cells.