Differential effects of GVHD therapies on intestinal epithelium

ABSTRACT: Graft-versus-host disease (GVHD), an often-fatal complication of allogeneic hematopoietic cell transplantation, is driven by inflammatory injury that damages target organs of the gastrointestinal (GI) tract, skin, and liver. Effective therapies must not only suppress GVHD reactivity of donor lymphocytes but also permit regeneration of the damaged epithelium, particularly in the GI tract. Systemic corticosteroids are the standard first-line treatment for GVHD because of 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), which are critical for maintaining gut integrity and barrier function, are key cellular targets of GVHD. We used 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, whereas 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.