Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice Journal Article

Authors: Rotolo, J.; Stancevic, B.; Zhang, J.; Hua, G.; Fuller, J.; Yin, X.; Haimovitz-Friedman, A.; Kim, K.; Qian, M.; Card├│-Vila, M.; Fuks, Z.; Pasqualini, R.; Arap, W.; Kolesnick, R.
Article Title: Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice
Abstract: Radiation gastrointestinal (GI) syndrome is a major lethal toxicity that may occur after a radiation/nuclear incident. Currently, there are no prophylactic countermeasures against radiation GI syndrome lethality for first responders, military personnel, or remediation workers entering a contaminated area. The pathophysiology of this syndrome requires depletion of stem cell clonogens (SCCs) within the crypts of Lieberk├╝hn, which are a subset of cells necessary for postinjury regeneration of gut epithelium. Recent evidence indicates that SCC depletion is not exclusively a result of DNA damage but is critically coupled to ceramide-induced endothelial cell apoptosis within the mucosal microvascular network. Here we show that ceramide generated on the surface of endothelium coalesces to form ceramide-rich platforms that transmit an apoptotic signal. Moreover, we report the generation of 2A2, an anti-ceramide monoclonal antibody that binds to ceramide to prevent platform formation on the surface of irradiated endothelial cells of the murine GI tract. Consequently, we found that 2A2 protected against endothelial apoptosis in the small intestinal lamina propria and facilitated recovery of crypt SCCs, preventing the death of mice from radiation GI syndrome after high radiation doses. As such, we suggest that 2A2 represents a prototype of a new class of anti-ceramide therapeutics and an effective countermeasure against radiation GI syndrome mortality.
Keywords: controlled study; unclassified drug; nonhuman; radiation dose; animal cell; mouse; apoptosis; animal experiment; animal model; stem cell; monoclonal antibody; endothelium cell; irradiation; antigen binding; gastrointestinal disease; clonogenesis; ceramide; intestine crypt; lamina propria; monoclonal antibody 2a2; radiation gastrointestinal syndrome; stem cell clonogen
Journal Title: Journal of Clinical Investigation
Volume: 122
Issue: 5
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2012-05-01
Start Page: 1786
End Page: 1790
Language: English
DOI: 10.1172/jci59920
PROVIDER: scopus
PMCID: PMC3336980
PUBMED: 22466649
Notes: --- - "Export Date: 4 June 2012" - "CODEN: JCINA" - "Source: Scopus"
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MSK Authors
  1. Zvi Fuks
    309 Fuks
  2. Jianjun Zhang
    7 Zhang
  3. Xianglei Yin
    9 Yin
  4. Richard N Kolesnick
    235 Kolesnick
  5. Guoqiang Hua
    16 Hua
  6. Jimmy A Rotolo
    31 Rotolo
  7. John David Fuller
    7 Fuller