Effect of IL-22 on intestinal stem cells, GVHD-related tissue damage, and GVL.

Abstract

6539 Background: Intestinal graft vs. host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (allo-BMT). Strategies to limit GVHD by selective promotion of epithelial regeneration in the absence of immunosuppression are largely unknown. Methods: We investigated the role of IL-22 in allo-BMT by utilizing wild type and IL-22 knockout (KO) mice as donors or recipients in allo-BMT. Results: We found that administration of an anti-IL-22 neutralizing antibody to allo-BMT recipients during the first month post-BMT led to increased GVHD mortality, indicating that IL-22 functioned to reduce GVHD severity post-BMT. In contrast, use of IL-22 KO donor T cells did not impair their ability to eliminate A20 lymphoma cells upon tumor challenge, thus indicating that IL-22 was not essential for donor T cells to mediate graft vs. lymphoma (GVL) responses. BMT with WT donors and recipients indicated that IL-22 levels in small and large intestine were increased after BMT and after radiation injury (RI) without BMT. IL-22 upregulation after RI was dependent on the presence of IL-23p40. Although intestinal IL-22 levels were increased after T cell-depleted (TCD) BMT, intestinal IL-22 was reduced by GVHD, as IL-22 production was mediated by host-derived innate lymphoid cells (ILC) that were eliminated by GVHD. Furthermore, host-derived IL-22 was critical for reduction of GVHD morbidity, mortality, and intestinal pathology. GVHD in IL-22 KO mice led to increased apoptosis in epithelial crypts where the intestinal epithelial stem/progenitor cell niche is located. Immunohistochemistry and immunofluorescence demonstrated IL-22 receptor expression on intestinal stem cells (ISC) and progenitors. Allo-BMT in Lgr5-LacZ reporter mice indicated that ISC were targeted by GVHD, and GVHD in IL-22 KO mice led to dramatic ISC depletion. Conclusions: IL-22 is critical for protection of host epithelium during GVHD and critical for protection of ISC, and it does not contribute to donor T cell GVL responses. These findings may have broad relevance for protection of ISC and intestinal epithelium in clinical GVHD and other inflammatory intestinal diseases, and may be useful for clinical separation of pathologic GVH and therapeutic GVL responses.