The use of high doses of the anti-cancer drug methotrexate (MTX) is associated with intestinal damage. As a result, mucosal immune cells become increasingly exposed to a vast amount of microbial stimuli. We aimed at determining whether these cells are still functional during MTX treatment. Furthermore, we assessed if activation of the mucosal immune system would play a role in the pathogenesis of mucositis. A contributive role to mucositis for the adaptive immune system was established by showing that mucosal lymphocytes from MTX-treated mice secreted enhanced amounts of cytokines upon ex vivo polyclonal stimulation. Next, in vitro experiments revealed that macrophages were not affected by MTX in the capacity to produce tumor necrosis factor-alpha (TNF-alpha) and IL-10 after LPS exposure. Moreover, peritoneal macrophages from MTX-treated mice produced more IL-10 and TNF-alpha upon LPS stimulation, compared with cells derived from control mice. These data indicate a persistence of both innate and adaptive immune responses in this model. The clinical relevance of these findings was further established by the fact that LPS exposure prior to MTX treatment aggravated the course of mucositis. Furthermore, LPS-responsive mice recovered more slowly compared with LPS-unresponsive mice from MTX treatment. Finally, we found an increase in weight loss and intestinal damage upon MTX treatment in IL-10-deficient mice in comparison to wild-type controls, suggesting a protective role for IL-10 in mucositis. We conclude that mucosal immune responses remain resilient during MTX-induced mucositis. Whereas TNF-alpha production may contribute to mucosal damage, IL-10 may regulate by restricting excessive mucositis.
This study demonstrates that local colonic application of tacrolimus 2-4 mg daily in patients with refractory distal colitis is feasible, probably safe, and potentially efficacious, and therefore opens the need for a further, randomized trial.
Natural killer T (NKT) cells are a subset of lymphocytes that express cell surface molecules of both conventional T cells and natural killer cells and share the features of both innate and adaptive immune cells. NKT cells have been proposed to make both protective and pathogenic contributions to inflammatory bowel diseases (IBD). On the one hand, recent studies have shown that these cells are involved in the maintenance of mucosal homeostasis. On the other, NKT cells were shown to play a pathogenic role in human ulcerative colitis. Similar contrasting data have been generated in murine models of IBD. Whether the apparent differences in NKT response patterns depend on variations in NKT antigens and/or on the presence of specific subsets of mucosal NKT cells remains to be elucidated. In this article we review the current literature on intestinal NKT cells and their roles in IBD pathogenesis. Specifically, the nomenclature, NKT antigens, and immune mechanisms of NKT cells within the intestinal mucosa are discussed.
Inflammatory bowel diseases (IBDs) are thought to result from unopposed immune responses to normal gut flora in a genetically susceptible host. A variety of immunomodulating therapies are applied for the treatment of patients with IBDs. The first-line treatment for IBDs consists of 5-aminosalicylate and/or budesonide. However, these first-line therapies are often not suitable for continuous treatment or do not suffice for the treatment of severe IBD. Recently, efforts have been made to generate novel selective drugs that are more effective and have fewer side effects. Despite promising results, most of these novel drugs are still in a developmental stage and unavailable for clinical application. Yet, another class of established immunomodulators exists that is successful in the treatment of inflammatory bowel diseases. While waiting for emerging novel therapies, the use of these more established drugs should be considered. Furthermore, one of the advantages of using established immunomodulators is the well-documented knowledge on the long-term side effects and on the mechanisms of action. In this review, the authors discuss 3 well-known immunomodulators that are being applied with increased frequency for the treatment of IBD: tacrolimus, methotrexate, and mycophenolate mofetil. These agents have been used for many years as treatment modalities for immunosuppression after organ transplantation, for the treatment of cancer, and for immunomodulation in several other immune-mediated diseases. First, this review discusses the potential targets for immunomodulating therapies in IBDs. Second, the immunomodulating mechanisms and effects of the 3 immunomodulators are discussed in relationship to these treatment targets.
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