Proposed mechanisms by which MSCs may treat and prevent aGVHD during pathogenesis. The 3 stages of aGVHD pathogenesis provide opportunities for IV-infused MSCs for prophylaxis and treatment, through cell-cell contact or secreted mediators. First, tissue injury induced by the conditioning regimen (radiation and/or chemotherapy) causes inflammation and secretion of inflammatory cytokines. MSCs migrate to these sites of inflammation where they may limit tissue damage and promote healing and tissue regeneration. Second, following HCT, donor T cells are activated by host antigen-presenting cells (APCs), and MSCs may traffic to sites of alloactivation and suppress proliferation of activated T cells. Third, activated donor T cells target host tissue immune injury. Although less is known about how MSCs act in the third stage, MSCs could migrate to sites of graft-versus-host interactions and inhibit the local immune response. CTL, cytotoxic T lymphocyte.