Abstract
The use of anti-toxin human monoclonal antibodies (HMab) as treatment for C. difficile infection has been investigated in animal models and human clinical trials as an alternative to or in combination with traditional antibiotic therapy. While HMab therapy appears to be a promising option, how systemically administered IgG antibodies protect the colonic mucosa during Clostridium difficile infection is unknown. Using the gnotobiotic piglet model of Clostridium difficile infection, we administered a mixture of anti-TcdA and anti-TcdB HMabs systemically to piglets infected with either pathogenic or non-pathogenic C. difficile strains. The HMabs were present throughout the small and large intestinal tissue of both groups, but significant HMabs were present in the lumen of the large intestines only in the pathogenic strain-infected group. Similarly, HMabs measured in the large intestine over a period of 2–4 days following antibody administration were not significantly different over time in the gut mucosa among the groups, but concentrations in the lumen of the large intestine were again consistently higher in the pathogenic strain-infected group. These results indicate that systemically administered HMab IgG reaches the gut mucosa during the course of CDI, protecting the host against systemic intoxication, and that leakage through the damaged colon likely protects the mucosa from further damage, allowing initiation of repair and recovery.
Highlights
Clostridium difficile is an anaerobic, spore-forming, grampositive bacterium, and the most frequent cause of antibioticassociated diarrhea in humans
Piglets treated with a mixture of CDA1 and CDB1 two days after inoculation with the UK6 strain of C. difficile were protected from development of severe clinical signs of C. difficile infection (CDI) as well as severe injury to the colonic mucosa, systemic intoxication, and mortality, compared with the UK6-infected, irrelevant anti-Stx2 human monoclonal antibodies (HMab) treated controls (Table 1), as well as untreated UK6-infected piglets, which we have previously described [7,13]
The anti-toxin HMabs used in these experiments have been shown to be effective in modifying the clinical outcome of CDI in the hamster and gnotobiotic piglet models, and in clinical trials with human patients [5,6,11,12]
Summary
Clostridium difficile is an anaerobic, spore-forming, grampositive bacterium, and the most frequent cause of antibioticassociated diarrhea in humans. C. difficile is a toxin-producer, and pathogenic effects are due primarily to the two large clostridial glucosylating toxins, toxin A (TcdA) and toxin B (TcdB). These toxins are enterotoxic and cause increased mucosal permeability by inducing intestinal epithelial cell damage [1]. Both TcdA and TcdB consist of three major domains: the Nterminal catalytic domain, the central translocation domain, and the C-terminal receptor binding domain [2]. Human monoclonal antibodies (HMab) against TcdA and/or TcdB effectively treat CDI in the hamster model [6] as well as in the piglet model in our laboratory [7], and, in combination with either metronidazole or vancomycin, significantly reduce CDI recurrence rate in humans [5]
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