Intestinal damage and myosin light chain kinase (MLCK)‐dependent epithelial barrier dysfunction drive minor mismatch graft‐versus‐host disease (GVHD)

Abstract

GVHD, a serious complication of bone marrow transplantation (BMT), targets the intestine, liver, and skin. Some have suggested that the intestine may also be a site of GVHD initiation. To test this, we developed a model of minor mismatch GVHD by 129 (H-2b) BMT into lethally irradiated B6 (H-2b) recipients. We found that adoptive transfer (AT) of 129 splenocytes, without bone marrow, into sublethally irradiated B6/Rag1−/− mice also caused GVHD, but AT into unconditioned B6/Rag1−/− did not. This difference was not due to graft rejection. Moreover, donor cells in irradiated recipients demonstrated increased in vivo alloreactivity to labeled B6 targets compared to unconditioned recipients. This suggests that radiation-dependent priming is required for GVHD. To determine if intestinal damage, as occurs with radiation, contributes to GVHD, mild colonic injury was induced with DSS prior to 129 AT. DSS + 129 AT mice developed systemic GVHD as well as increased alloreactivity to B6 targets. Thus, intestinal damage is required for minor mismatch GVHD. Moreover, MLCK knockout or constitutively active-MLCK transgenic B6 mice developed less and more severe GVHD, respectively, after 129 BMT with lethal irradiation. We conclude that intestinal epithelial barrier dysfunction, initiated by conditioning and perpetuated by MLCK-dependent epithelial barrier dysfunction, drives minor mismatch GVHD. Supported by NIH.