title: Mesenchymal stromal (stem) cells suppress pro-inflammatory cytokine production but fail to improve survival in experimental staphylococcal toxic shock syndrome.
abstract: BACKGROUND
  Toxic shock syndrome (TSS) is caused by an overwhelming host-mediated response to bacterial superantigens produced mainly by Staphylococcus aureus and Streptococcus pyogenes. TSS is characterized by aberrant activation of T cells and excessive release of pro-inflammatory cytokines ultimately resulting in capillary leak, septic shock, multiple organ dysfunction and high mortality rates. No therapeutic or vaccine has been approved by the U.S. Food and Drug Administration for TSS, and novel therapeutic strategies to improve clinical outcome are needed. Mesenchymal stromal (stem) cells (MSCs) are stromal cells capable of self-renewal and differentiation. Moreover, MSCs have immunomodulatory properties, including profound effects on activities of T cells and macrophages in specific contexts. Based on the critical role of host-derived immune mediators in TSS, we hypothesized that MSCs could modulate the host-derived proinflammatory response triggered by Staphylococcal enterotoxin B (SEB) and improve survival in experimental TSS.
  
  
  METHODS
  Effects of MSCs on proinflammatory cytokines in peripheral blood were measured in wild-type C57BL/6 mice injected with 50 μg of SEB. Effects of MSCs on survival were monitored in fatal experimental TSS induced by consecutive doses of D-galactosamine (10 mg) and SEB (10 μg) in HLA-DR4 transgenic mice.
  
  
  RESULTS
  Despite significantly decreasing serum levels of IL-2, IL-6 and TNF induced by SEB in wild-type mice, human MSCs failed to improve survival in experimental TSS in HLA-DR4 transgenic mice. Similarly, a previously described downstream mediator of human MSCs, TNF-stimulated gene 6 (TSG-6), did not significantly improve survival in experimental TSS. Furthermore, murine MSCs, whether unstimulated or pre-treated with IFNγ, failed to improve survival in experimental TSS.
  
  
  CONCLUSIONS
  Our results suggest that the immunomodulatory effects of MSCs are insufficient to rescue mice from experimental TSS, and that mediators other than IL-2, IL-6 and TNF are likely to play critical mechanistic roles in the pathogenesis of experimental TSS.
authors.forename: Hani
authors.initials: H
authors.lastname: Kim
authors.forename: Ilyse
authors.initials: I
authors.lastname: Darwish
authors.forename: Maria-Fernanda
authors.initials: MF
authors.lastname: Monroy
authors.forename: Darwin J
authors.initials: DJ
authors.lastname: Prockop
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.affiliation: Sandra A, Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, M5G 1 L7, Canada. kevin.kain@uhn.ca.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D012772:Shock, Septic / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D013203:Staphylococcal Infections / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality
chemical_list: D016207:Cytokines; D004768:Enterotoxins; D018836:Inflammation Mediators; C031818:enterotoxin B, staphylococcal