Differential effects of GVHD therapies on intestinal epithelium

Graft-versus-host disease (GVHD), an often-fatal complication of allogeneic hematopoietic stem cell transplantation (HCT), is driven by inflammatory injury that damages target organs of gastrointestinal (GI) tract, skin and liver. Effective therapies must not only suppress GVHD reactivity of donor lymphocytes but permit regeneration of the damaged epithelium, particularly in the GI tract. Systemic corticosteroids are the standard first-line treatment for GVHD due to their powerful immunosuppressive and anti-inflammatory properties but may retard epithelial repair. Ruxolitinib, a selective JAK1/2 inhibitor, is an approved therapy for steroid-refractory GVHD, although its direct effects on epithelial repair are unknown. Intestinal stem cells (ISCs) that are critical for maintaining gut integrity and barrier function are key cellular targets of GVHD. We employed both ileal and colonic organoid cultures to study the direct effects of methylprednisolone and ruxolitinib under conditions that controlled the strength of the GVH reaction. Ruxolitinib prevented inflammatory apoptosis in both human and murine organoids and preserved ISC function and proliferation, while corticosteroids offered no protection and in fact suppressed proliferation. This study highlights the importance of GVHD therapies that facilitate epithelial repair and regeneration, protect target tissues and suppress alloreactivity of donor T cells.