Epithelial regeneration during graft-versus-host disease

Abstract

Allogeneic bone marrow transplantation is a potentially curative therapy for a variety of malignant and non-malignant hematological diseases. Graft versus host disease (GVHD) is a major complication resulting in significant post-transplant morbidity and mortality. GVHD is primarily mediated by allo-reactive donor derived T cells. In recent years a number of studies have shown that the epithelial cells in GVHD target organs are specifically attacked by these allo reactive T cells. We have demonstrated an important regenerative loop in both the intestines and the thymus which involves the activation of tissue specific dendritic cells releasing IL-23 to stimulate tissue specific innate lymphoid cells type 3 to produce IL-22, which operates as a trophic factor to restore epithelial damage. However, during GVHD, allo reactive T cells not only directly lyse epithelial cells, but also eliminate host derived innate lymphoid cells type 3 and in this way impair this important regenerative mechanism. Our preliminary data indicate that a similar mechanism might be operational in the liver. We are currently exploring the use of IL-22 administration as an additional treatment in combination with corticosteroids both in mouse and man. Allogeneic bone marrow transplantation is a potentially curative therapy for a variety of malignant and non-malignant hematological diseases. Graft versus host disease (GVHD) is a major complication resulting in significant post-transplant morbidity and mortality. GVHD is primarily mediated by allo-reactive donor derived T cells. In recent years a number of studies have shown that the epithelial cells in GVHD target organs are specifically attacked by these allo reactive T cells. We have demonstrated an important regenerative loop in both the intestines and the thymus which involves the activation of tissue specific dendritic cells releasing IL-23 to stimulate tissue specific innate lymphoid cells type 3 to produce IL-22, which operates as a trophic factor to restore epithelial damage. However, during GVHD, allo reactive T cells not only directly lyse epithelial cells, but also eliminate host derived innate lymphoid cells type 3 and in this way impair this important regenerative mechanism. Our preliminary data indicate that a similar mechanism might be operational in the liver. We are currently exploring the use of IL-22 administration as an additional treatment in combination with corticosteroids both in mouse and man.