Editorial: An apple a day keeps colitis away

IBD often presents in childhood and persists throughout life [1]. CD and UC are the best-known forms and carry an elevated risk of colon cancer [2]. Dysfunction of the intestinal immune system is a major mechanism by which chronic inflammation occurs in colitis. Failure to regulate T cell responses in the intestinal or colonic mucosa leads to an inappropriate and sustained immunologic reaction, causing tissue injury. As a result of recent advances in the understanding of the mechanisms underlying IBD, there have been several drugs introduced into the market over the past 20 years. These conventional colitis treatments reduce periods of active disease and maintain remission, but treatment outcomes are often marginal, patients become refractory, and there are dangerous side-effects, including cancer and death. It is thought that these side-effects result, in part, because some of the drugs have broad specificity and do not target any single type of white blood cell (e.g., corticosteroids). Those therapeutics that do target a specific molecule (e.g., TNFinhibitors) may act as double-edged swords because of the pleiotropic functions of their targets. Therefore, although they have beneficial effects in the arena of IBD, they also adversely affect the proper function of organs/ tissues in other parts of the body. Consequently, there is a need to identify new targets for therapeutic intervention and molecules that have potent antiinflammatory properties with minimal toxicity. The use of CAMs remains a promising means for abating symptoms of active disease, with few (and often no) side-effects at efficacious doses. We have only recently begun to elucidate the mechanisms of CAM actions. One likely reason for their success at preventing and/or treating diseases such as IBD is that CAMs do not completely knock out any single player in inflammation (e.g., iNOS, COX-2, TNF, cytokines, NFB) but have ubiquitous properties that modestly suppress multiple players. Another possible reason being explored is that CAMs (single molecules and extracts) may be able to target a single white blood cell or a subset of white blood cell populations that drive diseases such as IBD. In this issue of the Journal of Leukocyte Biology, Skyberg et al. [3] have carried out extensive and elegant experiments to show suppression of DSS-induced colitis in mice by APPs (1500 mg/kg/ day; the human equivalent of 122 mg/ kg/day). This study not only complements other studies in rats and mice [4, 5] but also has advanced the field of CAMs and their modulation of chronic inflammatory diseases such as colitis. Using a variety of knockout mice, as well as antibody-depletion studies, Skyberg et al. [3] conclude that APP-mediated protection of DSS-induced colitis requires TCR T cells and provide preliminary evidence that protection may be through the regulation of IFNmediated recruitment of CXCR3 TCR T cells to the colon. Although this hypothesis should be explored further, it is also possible that there are additional mechanisms by which APP targets TCR T cells. For example, APP may provide protection from colitis via targeted induction of TCR T cell apoptosis (possibly of tissue-specific effector memory T cells; Fig. 1). Several different CAMs have been shown to induce apoptosis in CD4 /CD25 T cells in vitro and in vivo [6, 7]. As acknowledged by the authors, the precise subset(s) of TCR T cells targeted by APP remain to be identified conclusively. In light of the finding that colitis occurs after transfer of primary splenic TCR CD4 CD45RB T cells into SCID mice [8] (i.e., an adoptive transfer model of colitis), one hypothesis is that such a subtype may be one of the targets of APP, although from the CD4 depletion experiments, it is clear that there are other players involved in the DSS model. It is intriguing to speculate that a regulatory subpopulation of TCR T cells may also be affected by APP treatment. In their antibody-depletion experiments, the authors provide some evidence that there may be a partial requirement for a CD4/ CD8/TCR subset of cells for APP-mediated protection, which may act to reduce inflammatory cytokines such as IFN. In future studies, it will be interesting to determine whether this population