Genetics of Intestinal Graft-Versus-Host Disease

Abstract SCI-51

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapy with curative potential for a variety of malignant and nonmalignant diseases. Despite standard prophylactic regimens, graft-versus-host disease (GVHD) continues to limit the success of outcomes in allo-HSCT patients. Gastrointestinal (GI) GVHD is the predominant contributor to acute GVHD-related mortality. The pathophysiology of GI GVHD has unique features that are related to the important interactions between the donor allograft (especially donor alloreactive T cells), mucosal adaptive and innate intestinal immunity, intestinal epithelial homeostasis, and the intestinal microbial flora. The pathophysiology of intestinal GVHD has many similarities with inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis (UC). At last count, 99 susceptibility loci/genes for Crohn’s and UC have been published. Multiple genes are involved in IL-23/Th17 signaling, defective processing of intracellular bacteria involving autophagy and innate immunity (including NOD2 and ATG16L1), and defects in barrier function and shared susceptibility with other autoimmune diseases (such as type 1 and 2 DM). Early studies in mice and in patients suggested a link between an individual’s intestinal microbial flora and his/her propensity for GVHD resulting in varying protocols for gut decontamination, which continue at some centers to this date. We will discuss the latest data regarding the role in intestinal GVHD of genetic changes in the before-mentioned pathways and genes in the donor and host, as well as its interactions with the intestinal flora.