Natural History and Pathophysiology of Gastrointestinal Graft-versus-Host Disease

Graft-versus-host disease (GVHD) affects up to 70% of patients who undergo stem cell transplantation. GVHD is associated with significant morbidity and mortality, and commonly affects the skin, liver, and gastrointestinal (GI) system. Gastrointestinal (GI) manifestations of GVHD include anorexia, nausea, vomiting, abdominal pain, and diarrhea. In patients with GI GVHD, the extent of gut involvement and its relationship to underlying symptoms is unclear. Furthermore, diagnosis requires histologic evaluation that entails cumbersome invasive endoscopic procedures for tissue procurement. Histologic findings that support this diagnosis are nonspecific and have poor sensitivity and specificity. Treatment of GI GVHD is also nonspecific, and has many systemic side effects that account for a large portion of associated morbidity and mortality.

Such uncertainties regarding the diagnosis and treatment of GI GVHD stem from a lack of understanding of the pathophysiology of the disease. Cytokines produced by T lymphocytes, mononuclear phagocytes, and natural killer cells have been shown to play an integral role in the regulation of tissue damage. Human studies performed to date have examined peripheral blood cytokines, but results have been conflicting and with little clinical correlation. Current analysis of gut tissue has been limited mostly to animal subjects with little correlation to humans.

The primary objective of this study is to identify areas of the GI tract to be biopsied that would achieve the highest yield for the diagnosis of GI GVHD. This will be accomplished by performing esophagogastroduodenoscopy, colonoscopy, and ileoscopy in all post transplant patients with GI symptoms, suspected to be due to GVHD. Endoscopic biopsies will be evaluated by a single designated GI pathologist to make the diagnosis of GVHD. A novel application of a quantitative histological apoptotic assay will be evaluated in a blinded fashion for its diagnostic utility. A GVHD diagnostic yield rate for each area of the GI tract will be the primary outcome measure.

Other biopsies obtained at baseline, following the conditioning regimen as well as before and after therapy for GI GVHD will be used to achieve the secondary objective of understanding the immune response underlying GI GVHD. A comprehensive evaluation of the inflammatory milieu of gut tissues will be achieved using immunohistochemistry and flow cytometric immunophenotyping of mucosal mononuclear cells and microarray, qRT-PCR and ELISA of mucosal cytokines. Other secondary objectives include the evaluation of serum proteomic pattern analysis, serum citrulline, fecal calprotectin and 18F-FDG PET/CT for the noninvasive diagnosis of GI GVHD.

Better understanding of the pathophysiology of GI GVHD will allow us to develop more focused and effective diagnostic and therapeutic options that are less invasive and have fewer systemic side effects leading to reduced morbidity and mortality.