Tissue tolerance: a distinct concept to control acute GVHD severity

Target tissue damage occurs as a consequence of pathological immune responses following allogeneic stem cell transplantation resulting in acute graft-versus-host disease (GVHD). Among those who study infections in plants, it is well recognized that tissues play a distinct role from the immune system in mediating disease severity. Recently, this has also been appreciated in mammals. However, the severity of immunopathology in the context of alloimmune diseases such as acute GVHD has been mainly understood and managed by direct targeting of immune cells to generate immune tolerance. The role of tissue-intrinsic factors that might contribute to regulation of acute GVHD severity has been largely overlooked. Here, we introduce the concept of "tissue tolerance" to discuss the tissue-specific programs that contribute to target tissue resilience, repair, and regeneration, and mitigate severity of acute GVHD without altering the load or function of alloreactive immune cells.