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.

- INCLUSION CRITERIA:

All patients 18 years or older who have undergone or plan to undergo any type of
allogeneic bone marrow or peripheral stem cell transplant. (This will be coordinated with
all different institutes at NIH to involve patients who participate in NIH affiliated
protocols.)

EXCLUSION CRITERIA:

1. Patients who are under the age of 18 years.

2. Patients with a platelet count less than 30,000/mm(3).

3. Patients with an elevated prothrombin or partial thromboplastin time more than 1.5
times greater than the upper limit of normal or an absolute neutrophil count less
than 500/mm(3) of blood or a history of a bleeding diathesis.

4. Women who are pregnant, as determined by laboratory evaluation performed according to
the referring transplant protocol, or breast feeding.

5. Patients who are unable to provide informed consent.