Anti-CD3–induced diarrhea is associated with edema and increased numbers of intraepithelial lymphocytes but not ulceration or epithelial apoptosis. (A) Macroscopic examination of the small intestinal mucosae 3 hours after anti-CD3 injection showed distortion of the normal mucosal folds by edema and luminal fluid accumulation. Notably, anti-CD3 injection did not result in mucosal ulceration or erosion (scale bar, 1 mm). (B) Microscopic examination of the small intestinal mucosae revealed mild villous thickening 3 hours after anti-CD3 injection. An increase in the number of intraepithelial lymphocytes (arrows) was also present (5.1 ± 0.2 intraepithelial lymphocytes per 100 epithelial cells in control tissue vs. 7.9 ± 0.3 intraepithelial lymphocytes per 100 epithelial cells 3 hours after anti-CD3 injection; P < 0.0001), but there was no apparent epithelial damage or ulceration (scale bar, 100 μm). (C) Closer examination of the crypts showed mitotic figures in both control and anti-CD3–treated jejunum, but apoptotic cells were rare both before and 3 hours after anti-CD3 treatment (scale bar, 10 μm). (D) Quantitative analysis of apoptotic epithelial cells revealed no significant increase in number 3 hours after anti-CD3 injection. (E) Immunoblots for caspase-3 in isolated small intestinal epithelial cells 3 hours after vehicle or anti-CD3 injection detected only the uncleaved (inactive) form of this protein, indicating minimal caspase-3 activation.