Translational Clinical Strategies for the Prevention of Gastrointestinal Tract Graft Versus Host Disease

Abstract

Graft versus host disease (GVHD) is the major non-relapse complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). Unfortunately, GVHD occurs in roughly half of patients following this therapy and can induce severe life-threatening side effects and premature mortality. The pathophysiology of GVHD is driven by alloreactive donor T cells that induce a proinflammatory environment to cause pathological damage in the skin, gastrointestinal (GI) tract, lung, and liver during the acute phase of this disease. Recent work has demonstrated that the GI tract is a pivotal target organ and a primary driver of morbidity and mortality in patients. Prevention of this complication has therefore emerged as an important goal of prophylaxis strategies given the primacy of this tissue site in GVHD pathophysiology. In this review, we summarize foundational pre-clinical studies that have been conducted in animal models to prevent GI tract GVHD and examine the efficacy of these approaches upon subsequent translation into the clinic. Specifically, we focus on therapies designed to block inflammatory cytokine pathways, inhibit cellular trafficking of alloreactive donor T cells to the GI tract, and reconstitute impaired regulatory networks for the prevention of GVHD in the GI tract.

Influence of Housing Temperature and Genetic Diversity on Allogeneic T Cell-Induced Tissue Damage in Mice

“…The vast majority of mouse models of GVHD use inbred mice that are housed at ST. Although these studies have provided new and promising data regarding the immunopathological mechanisms responsible for aGVHD, the translation of these data into more effective therapeutics for treatment of patients has been rather poor [17][18][19][20]. Although the reasons for this dismal bench-to-bedside transition are not completely understood, it is known that immune responses in mice housed at ST (22-24 • C) may be quite different than mice housed at their TNT (30-32 • C).…”

“…These preclinical studies have been instrumental in helping to define many of the immunopathological mechanisms responsible for disease development and revealing novel therapeutic targets for more effective drug development. Despite these promising findings, the translation of these experimental data into more effective therapeutics for the treatment of patients has been poor [17][18][19][20].…”

Diagnostic prediction of gastrointestinal graft-versus-host disease based on a clinical- CT- signs nomogram model

“…Hematopoietic stem cell transplantation (HSCT) helps counteract the effects of tumor and disease, and thus, it is essential for the management of several life-threatening hematological diseases [1,2]. Graft-versus-host disease (GVHD) can occur after HSCT, and is an immune response resulting from the interaction between donor and recipient cells.…”