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 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.
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Rotolo
authors.forename: Branka
authors.initials: B
authors.lastname: Stancevic
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Hua
authors.forename: John
authors.initials: J
authors.lastname: Fuller
authors.forename: Xianglei
authors.initials: X
authors.lastname: Yin
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
authors.forename: Kisu
authors.initials: K
authors.lastname: Kim
authors.forename: Ming
authors.initials: M
authors.lastname: Qian
authors.forename: Marina
authors.initials: M
authors.lastname: Cardó-Vila
authors.forename: Zvi
authors.initials: Z
authors.lastname: Fuks
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.forename: Richard
authors.initials: R
authors.lastname: Kolesnick
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology* / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000528:radiation effects; D002417:Cattle; D002478:Cells, Cultured; D002518:Ceramides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism / Q000528:radiation effects; D004790:Enzyme Induction / Q000528:radiation effects; D005767:Gastrointestinal Diseases / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D021962:Membrane Microdomains / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011833:Radiation Injuries, Experimental / Q000473:pathology / Q000517:prevention & control*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D002518:Ceramides; D013108:Sphingomyelin Phosphodiesterase