1. Single administration of p2TA (AB103), a CD28 antagonist peptide, prevents inflammatory and thrombotic reactions and protects against gastrointestinal injury in total-body irradiated mice.
- Author
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Mirzoeva S, Paunesku T, Wanzer MB, Shirvan A, Kaempfer R, Woloschak GE, and Small W Jr
- Subjects
- Amino Acid Sequence, Animals, Antigens, Differentiation metabolism, CD28 Antigens chemistry, Cell Proliferation drug effects, Cell Proliferation radiation effects, Cyclin D1 metabolism, Cyclooxygenase 2 metabolism, Fibrinogen metabolism, Gamma Rays, Gastrointestinal Tract pathology, Gastrointestinal Tract radiation effects, Immunohistochemistry, Inflammation etiology, Inflammation metabolism, Interleukin-6 blood, Jejunum drug effects, Jejunum pathology, Jejunum radiation effects, Macrophages drug effects, Macrophages metabolism, Macrophages radiation effects, Male, Mice, Inbred BALB C, Mice, Inbred Strains, Radiation Injuries, Experimental complications, Radiation-Protective Agents pharmacology, Thrombosis blood, Thrombosis etiology, Whole-Body Irradiation, CD28 Antigens antagonists & inhibitors, Gastrointestinal Tract drug effects, Inflammation prevention & control, Peptides pharmacology, Thrombosis prevention & control
- Abstract
The goal of this study was to elucidate the action of the CD28 mimetic peptide p2TA (AB103) that attenuates an excessive inflammatory response in mitigating radiation-induced inflammatory injuries. BALB/c and A/J mice were divided into four groups: Control (C), Peptide (P; 5 mg/kg of p2TA peptide), Radiation (R; total body irradiation with 8 Gy γ-rays), and Radiation + Peptide (RP; irradiation followed by p2TA peptide 24 h later). Gastrointestinal tissue damage was evaluated by analysis of jejunum histopathology and immunohistochemistry for cell proliferation (Cyclin D1) and inflammation (COX-2) markers, as well as the presence of macrophages (F4/80). Pro-inflammatory cytokines IL-6 and KC as well as fibrinogen were quantified in plasma samples obtained from the same mice. Our results demonstrated that administration of p2TA peptide significantly reduced the irradiation-induced increase of IL-6 and fibrinogen in plasma 7 days after exposure. Seven days after total body irradiation with 8 Gy of gamma rays numbers of intestinal crypt cells were reduced and villi were shorter in irradiated animals compared to the controls. The p2TA peptide delivery 24 h after irradiation led to improved morphology of villi and crypts, increased Cyclin D1 expression, decreased COX-2 staining and decreased numbers of macrophages in small intestine of irradiated mice. Our study suggests that attenuation of CD28 signaling is a promising therapeutic approach for mitigation of radiation-induced tissue injury.
- Published
- 2014
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