LAUSR

Autophagy protects cells from a variety of stressors and is known to affect immune cell responses after allogeneic bone marrow transplant (allo-BMT). However, a definitive and exclusive role of target tissue pathways on mitigating graft-versus-host disease (GVHD) has yet to be demonstrated. Because GVHD target organs are under stress from alloreactive T cells, we sought to determine the role, if any, of target tissue autophagy in mitigating the severity of GVHD. Because the primary driver of morbidity and mortality after allo-BMT is gastrointestinal (GI) GVHD, we next hypothesized that autophagy protects the GI epithelium from alloimmune damage. To determine these effects in this target organ, we generated mice that lack a macroautophagy protein, ATG5, in the GI epithelium (Atg5D/IEC) and used them as recipients in the well-characterized MHC disparate GVHD murine model BALB/c→B6. As hypothesized, allo Atg5D/IEC mice showed significantly high mortality (P We next determined whether autophagy is critical for other GVHD target organs. To this end, we generated Atg5D/hep mice, which lack Atg5 expression in hepatocytes. Using the GVHD model described above, we observed dramatically shorter survival in the Atg5D/hep allo-recipients (P = 0.025) along with an increase in hepatocyte damage markers (bilirubin (P = 0.0001), alanine aminotransferase (P = 0.036), and alkaline phosphatase (P = 0.0002)) in Atg5D/hep allo-recipients. Again, there were similar numbers of splenic and liver-resident donor T cells, activation markers, and proinflammatory cytokines. To determine if autophagy is exclusively protective in GVHD target organs, we generated Atg5D/Myo mice, which lack Atg5 expression in cardiac myocytes, and Atg5D/Pod mice, which lack Atg5 expression in podocytes, in non-GVHD target organs. Using the same GVHD model as above, we monitored these mice and littermate controls for survival and severity of GVHD symptoms. In contrast to our findings in the Atg5D/hep and Atg5D/IEC recipients, we observed similar survival (P = 0.17, Myo; P = 0.49, Pod) and GVHD severity between these allo-recipients. Collectively, our results demonstrated that autophagy is a tissue-intrinsic protective response that regulates tissue damage severity only in GVHD target organs.