Contributions of mucosal immune cells to methotrexate-induced mucositis

Abstract

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.

Prophylactic ciprofloxacin treatment prevented high mortality, and modified systemic and intestinal immune function in tumour-bearing rats receiving dose-intensive CPT-11 chemotherapy

“…Thus, the effects of CPT-11 were compartmentalised with a primed local intestinal immunity and concomitantly suppressed systemic immunity. Our results are consistent with earlier findings (de Koning et al, 2006) that innate and adaptive immune responses of GALT cells were intact or even primed after high-dose methotrexate. CPT-11 has been consistently shown to disrupt GI integrity, and this may expose GALT cells to bacterial antigens and LPS.…”

“…CPT-11 has been consistently shown to disrupt GI integrity, and this may expose GALT cells to bacterial antigens and LPS. Hyper-responsiveness of intestinal local immune cells is considered to contribute to chemotherapy-induced gut injury (de Koning et al, 2006). Antigen-driven T-cell expansion in GALT may support the homeostasis of T-cell pools after depletion by chemotherapy (Dulude et al, 1997).…”

“…The activation and hyper-responsiveness of GALT cells contributes to the pathogenesis of chemotherapyinduced gut injury (de Koning et al, 2006). Excessive intestinal production of inflammatory cytokines (e.g., IL-1b, TNF-a, IFN-g) is critical for developing CPT-11-related GI toxicity (Zhao et al, 2004).…”

Emerging evidence on the pathobiology of mucositis

“…IL-10 is one of the more researched anti-inflammatory cytokines in mucositis. DeKoning and colleagues demonstrated that IL-10-deficient mice experience an increased weight loss and more severe intestinal damage following methotrexate treatment in comparison to wild-type controls [55]. Furthermore, cytokines directed at inhibiting pro-inflammatory cytokines may be useful as interventions for mucositis [56].…”

Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release

“…Chemotherapy is known to be capable of inducing an inflammatory cytokine response, which can lead to cytokine-induced sickness [27,42]. High dose MTX can induce mucositis, which is characterized by damage to the gastrointestinal mucosa [7]. This leads to a decreased barrier function and an enhanced risk of developing infections caused by micro-organisms originating from the intestines.…”