title: Human monoclonal antibodies against Clostridium difficile toxins A and B inhibit inflammatory and histologic responses to the toxins in human colon and peripheral blood monocytes.
abstract: Clostridium difficile infection (CDI) is a common and debilitating nosocomial infection with high morbidity and mortality. C. difficile mediates diarrhea and colitis by releasing two toxins, toxin A and toxin B. Since both toxins stimulate proinflammatory signaling pathways in human colonocytes and both are involved in the pathophysiology of CDI, neutralization of toxin A and B activities may represent an important therapeutic approach against CDI. Recent studies indicated that human monoclonal antibodies (MAbs) against toxins A and B reduce their cytotoxic and secretory activities and prevent CDI in hamsters. Moreover, anti-toxin A and anti-toxin B MAbs together with antibiotics also effectively reduced recurrent CDI in humans. However, whether these MAbs neutralize toxin A- and toxin B-associated immune responses in human colonic mucosa or human peripheral blood monocyte cells (PBMCs) has never been examined. We used fresh human colonic biopsy specimens and peripheral blood monocytes to evaluate the effects of these antibodies against toxin A- and B-associated cytokine release, proinflammatory signaling, and histologic damage. Incubation of anti-toxin A (MK3415) or anti-toxin B (MK6072) MAbs with human PBMCs significantly inhibited toxin A- and toxin B-mediated tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) expression. MK3415 and MK6072 also diminished toxin A- and toxin B-mediated NF-κB p65 phosphorylation in human monocytes, respectively, and significantly reduced toxin A- and B-induced TNF-α and IL-1β expression as well as histologic damage in human colonic explants. Our results underline the effectiveness of MK3415 and MK6072 in blocking C. difficile toxin A- and toxin B-mediated inflammatory responses and histologic damage.
authors: Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA.
authors: Hon Wai
authors: HW
authors: Koon
authors: David Q
authors: DQ
authors: Shih
authors: Tressia C
authors: TC
authors: Hing
authors: Jun Hwan
authors: JH
authors: Yoo
authors: Samantha
authors: S
authors: Ho
authors: Xinhua
authors: X
authors: Chen
authors: Ciarán P
authors: CP
authors: Kelly
authors: Stephan R
authors: SR
authors: Targan
authors: Charalabos
authors: C
authors: Pothoulakis
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D001427:Bacterial Toxins / Q000276:immunology*; D002478:Cells, Cultured; D016360:Clostridioides difficile / Q000276:immunology*; D003106:Colon / Q000187:drug effects / Q000276:immunology; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy / Q000517:prevention & control; D004768:Enterotoxins / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D053583:Interleukin-1beta / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D010766:Phosphorylation; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D053583:Interleukin-1beta; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile
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