Role of in vivo Activated T Cells in the Mechanisms of Villous Atrophy in Humans: Study of Allograft Rejection

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Abstract
Four children aged 6 months ot 9 years received fully HLA-mismatched ABO identical small intestinal allografts. In order to monitore the rejection process and to study epithelial changes induced by intestinal T cells activated by an allogeneic reaction, iterative biopsies were performed through the ileal enterostomy and processed for histology and immunohistochemistry. Episodes of acute histological reaction were observed in all 4 patients between day 10 and 160. It was preceded by appearance of pericryptic CD3+CD4+ or CD8+ T cells of recipient origin, increasing numbers of which expressed CD25. Simultaneously, early epithelial changes were noted: increased HLA-DR expression by enterocytes and decreased mitotic rate as shown by decreased numbers of KI67+ cells in crypts. During acute histological rejection, massive infiltration of mucosa by CD25+CD3+ T-cells and activated macrophages (KIM6+CD25+), was associated with crypt necrosis and then, destruction of surface epithelium. Successful treatment of graft rejection episodes with antilymphocytic serum (2), anti-CD3 monoclonal antibody (2), anti-CD25 monoclonal antibody (1) resulted in a rapid decrease of CD3+ cells, a more progressive decrease of CD25+ and KIM6+ macrophages, reappearance of KI67+ cells in crypts followed after a variable delay by recovery of villous architecture. Chronic histological rejection was observed in 1 patient after 7 months. It was characterized by total villous atrophy, fibrosis, endarteritis, infiltration of lamina propria and epithelium by CD3+CD8+ cells, a small number of which CD25+, strong HLA-DR expression by crypt and surface epithelium, increased numbers of KI67 enterocytes. Altogether these data suggested that activated T cells can induce two types of villous atrophy. One, observed in acute rejection, is associated to decreased epithelial cell renewal and epithelial destruction. The second one observed in chronic rejection is associated with increased epithelial cell renewal.

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