Involvement of alpha 1 and alpha 4 integrins in gut mucosal injury of graft-versus-host disease.

We have investigated the involvement of adhesion molecules in the lymphocyte infiltration associated with acute intestinal graft-versus-host disease (GVHD) induced by injection of C3H lymph node cells into irradiated (C3H x DBA/2)F1 mice. First we analyzed the expression profile of adhesion molecules including alpha 1, alpha 2, alpha 4, alpha 5, alpha 6, alpha L and beta 7 integrins, CD44 and L-selectin of lymphocytes from lymph nodes and gut mucosa in normal mice. In normal mice, intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL) uniquely showed increased expression of alpha 1, alpha 2 and beta 7 integrins, and decreased expression of L-selectin compared with that of lymphocytes of the lymph nodes and Peyer's patches. In mice with GVHD, IEL and LPL of donor lymph node cells origin underwent phenotypic changes characterized by the increased expression of alpha 1, alpha L and beta 7 integrins, and the loss of L-selectin. The expression profile of adhesion molecules on IEL and LPL of GVHD mice resembled that of normal mice except for the lack of alpha 2 integrin. Treatment of GVHD mice with anti-alpha 1, -alpha 4 or -beta 7 integrin antibody alone partially prevented the mucosal pathology of intestinal GVHD, whereas only mice treated with anti-alpha 1 showed reduced donor lymphocytic infiltration into the intestinal mucosa. In contrast, treatment with anti-alpha L or anti-CD44 antibody did not affect the intestinal GVHD. Furthermore, dual blockade of both alpha 1 and alpha 4 integrins completely inhibited the mucosal pathology and donor lymphocyte infiltration of intestinal GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)