Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice

Jimmy Rotolo, Branka Stancevic, Jianjun Zhang, Guoqiang Hua, John Fuller, Xianglei Yin, Adriana Haimovitz-Friedman, Kisu Kim, Ming Qian, Marina Cardó-Vila, Zvi Fuks, Renata Pasqualini, Wadih Arap, Richard Kolesnick

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

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 Lieberkühn, 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.

Original languageEnglish (US)
Pages (from-to)1786-1790
Number of pages5
JournalJournal of Clinical Investigation
Volume122
Issue number5
DOIs
StatePublished - May 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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