Deciphering the mechanisms of intestinal stem cell elimination by allogeneic T cells in order to develop novel GVHD treatment approaches
Pediatric and Adolescent Medicine
Final Report Abstract
Corticosteroids (CS) are the first-line treatment for gastrointestinal graft-versus-host disease (GI GVHD). Failure to respond to CS is associated with severe morbidity and poor survival. However, CS-mediated effects on intestinal epithelium during immune-mediated injury and regeneration are poorly understood. Although systemic CS administration improved survival after mouse allogeneic bone marrow transplantation (allo-BMT), we observed that GVHD-induced weight loss remained unchanged despite treatment. Postulating the presence of tissue-specific effects, we explored CS-mediated effects on GI epithelium during homeostasis and injury. We found that in vivo administration of CS reduced small intestine (SI) epithelial proliferation. Further modeling with ex vivo murine and human SI organoid cultures showed that CS culture directly inhibits proliferation of epithelial cells. CS also increased cytokine and T cell-induced organoid toxicity. In vivo treatment with CS after murine allo-BMT resulted in impaired epithelial regeneration and increased crypt loss. We found that IL-22 treatment overcame CS-mediated attenuation of organoid growth. IL-22 administration in murine allo-BMT models also rescued CS-induced impairment of epithelial regeneration. Our study thus demonstrates the rationale for combining immunosuppressive drugs and tissue supportive agents to develop successful strategies treating GI GVHD.
