Development of a T H17 immune response during the induction of murine syngeneic graft-versus-host disease

Abstract

Syngeneic graft-versus-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow (BM) and treatment with a 21 day course of the immunosuppressive agent cyclosporine A (CsA). Clinical symptoms of SGVHD appear 2–3 weeks post-CsA with inflammation occurring in the colon and liver. Previously we have demonstrated that CD4 + T cells and a T helper cell type 1 cytokine response (T H1) are involved in the development of SGVHD associated intestinal inflammation. Studies have recently discovered an additional T cell lineage that produces IL-17 and is termed T H17. It has been suggested that inflammatory bowel disease is a result of a T H17 response rather than a T H1 response. This study was designed to investigate T H17 involvement in SGVHD-associated colitis. Following induction of SGVHD, the levels of T H17 and T H1 cytokine mRNA and protein were measured in control and SGVHD animals. In vivo cytokine neutralization was performed to determine the role of the prototypic T H17 cytokine, IL-17, in the disease process. We found that during CsA-induced murine SGVHD there was an increase in both T H17 and T H1 mRNA and cytokines within the colons of diseased mice. The administration of an anti-mouse IL-17A mAb did not alter the course of disease. However, neutralization of IL-17A resulted in an increased production of IL-17F, a related family member, with an overlapping range of effector activities. These results demonstrate that in the pathophysiology of SGVHD, there is a redundancy in the T H17 effector molecules that mediate the development of SGVHD.