Intestinal crypt cell apoptosis in murine acute graft versus host disease is mediated by tumour necrosis factor α and not by the FasL-Fas interaction: effect of pentoxifylline on the development of mucosal atrophy

Abstract

Background-Murine T cell mediated acute semiallogeneic graft versus host disease (GVHD) is characterised by lymphocytic infiltrates, crypt hyperplasia, and villous atrophy. It has been shown that programmed cell death (apoptosis) of the crypt epithelium takes place during the intestinal manifestation of acute GVHD. Aims-To investigate which of the two most investigated inductors of apoptosis (Fas ligand (FasL) and tumour necrosis factor (TNF-)) is responsible for the induction of apoptosis in this animal model. Methods-Animals undergoing acute semiallogeneic GvH reaction were treated with neutralising anti-TNF-, two diVerent anti-FasL antibodies, or pentoxifylline.Results-Anti-TNF-application inhibited the appearance of apoptotic cells in the intestinal mucosa, whereas anti-FasL antibodies had no influence on mucosal apoptosis. In addition, the transfer of FasL deficient (gld) donor lymphocytes still induced crypt cell apoptosis, villous atrophy, and crypt hyperplasia. Furthermore, when the animals were treated with pentoxifylline, a known inhibitor of TNFsecretion in vitro and in vivo, there was significant normalisation of the intestinal morphology accompanied by inhibition of epithelial apoptosis. Conclusions-The FasL-Fas interaction is not involved in the induction of apoptosis during acute GVHD. However, neutralisation of TNF-by an antibody or by pentoxifylline inhibits the occurrence of apoptosis and of mucosal atrophy in this animal model. These results have implications for the treatment of immunologically mediated human atrophic gut diseases-for example, diet refractory cases of coeliac disease. (Gut 1999;45:229-235)

Intectin, a Novel Small Intestine-specific Glycosylphosphatidylinositol-anchored Protein, Accelerates Apoptosis of Intestinal Epithelial Cells

“…In certain inflammatory conditions, such as celiac disease, nematode infections, and graft-versus-host disease, the numbers of apoptotic nuclei were increased in villus epithelial cells (32)(33)(34)(35). In addition, the involvement of dysregulation of the apoptotic process in intestinal epithelial cells in inflammatory bowel diseases and colon cancer has also been suggested (36,37).…”

Importance of minor histocompatibility antigen expression by nonhematopoietic tissues in a CD4+ T cell–mediated graft-versus-host disease model

“…Early injury to the gut epithelium allows for the transmission of LPS into the systemic circulation and peripheral tissues, with subsequent activation of macrophages, and release of high levels IL-1 and TNF-α (31,32). Both of these inflammatory cytokines have established roles in the pathogenesis of lethal GVHD (26,30,(33)(34)(35)(36)(37). The finding that MHC class II expression by host nonhematopoietic target tissues in the [B6→B6.MHC II -/-] chimera was not essential for the cascade of inflammatory events that ultimately lead to GVHD and lethality (9) suggested that, in such models, either large amounts of systemic cytokines alone are sufficient to cause severe tissue injury, or resident allogeneic B6 APCs in the tissues are adequate to activate infiltrating T cells to mediate injury via localized cytokine production.…”

The Pathogenesis of Oral Lichen Planus

“…The role of TNF-␣ as a major effector molecule of GVHD has been confirmed in several experimental systems. Importantly, neutralizing anti-TNF-␣ antibodies have been shown to alleviate cutaneous and intestinal GVHD in both mice and humans (Piguet et al, 1987;Herve et al, 1992;Brown et al, 1999;Stuber et al, 1999). Blockade of the CD40-CD154 co-stimulatory pathway of antigen presentation prevented GVHD following allogeneic BMT (Durie et al, 1994;Blazar et al, 1998;Seung et al, 2000).…”