• Baboons affected by hereditary chronic diarrhea as a possible non-human primate model of celiac disease

      Fasano, Alessio; Kryszak, Deborah; Leland, Michelle; McGill, Henry C., 1921- (2006)
      Background: Celiac disease (CD) represents a unique model of autoimmunity in which, in contrast to most other autoimmune diseases, a close genetic association with HLA genes (DQ2 and/or DQ8), a highly specific humoral autoimmune response (autoantibodies to tissue transglutaminase, (TTG)), and, most importantly, the triggering environmental factor (gluten), are known. Given the undisputable role of gluten in causing inflammation and immune-mediated tissue damage, CD could provide unique opportunities to tackle the pathogenic basis of autoimmune processes. However, the lack of an animal model of the disease represents a major limitation in reaching goals. Aims: To establish if pedigreed colony of baboons with hereditary chronic diarrhea at the Southwest Foundation for Biomedical Research, could be used as a possible non-human primate model for celiac disease. Methods: Baboons from the pedigreed colony at the Southwest Foundation for Biomedical Research (SFBR) in San Antonio, Texas were reviewed. Those animals with chronic diarrhea (≥21 days) and more than two clinical admissions between January 1998 and December 2003 were selected. This search yielded 163 baboons. An infective cause of the diarrhea was ruled out. CD serology and intestinal histological analysis were performed on a selected number of animals. Results: The onset of diarrhea occurred at all ages (1-16 years of age) and was analyzed for distribution among the 4,200 offspring of 57 sires of the pedigreed colony. Fifty-one of the 163 cases (31%) of chronic diarrhea occurred among the offspring of 4 sires. Of the 20 cases studied, 5 (25%) tested TTG IgA and/or IgG antibodies positive, compared to 1/17 (5.9%) in healthy control baboons. Zonulin, a modulator of intestinal permeability that is up regulated in CD, resulted elevated in 8/20 (40%) baboons with chronic diarrhea and 0/17 controls. There was 80% correlation between positive TTG IgG and elevated zonulin. Duodenal samples obtained after the baboons were euthanized showed increased intraepithelial lymphocytes and, occasionally, marked lymphocytic mucosal infiltration and villi distortion and blunting. Four baboons with chronic diarrhea, weight loss, anemia, and histological findings of intestinal damage compatible with CD were individually caged and fed a gluten-free diet (GFD). After 6 weeks of diet the diarrhea persisted, however the animals began to gain weight. Conclusions: These preliminary observations suggest that a gluten-dependent enteropathy is present in the pedigreed baboon colony studied, and that it is clustered among the progeny of a few sires. This sire effect is presumptive evidence that the condition is hereditary. The clinical, serological, and histological features suggest a similarity to human CD and, therefore, that the progeny of this sire can be potentially used as a primate non-human model of CD.