Single administration of p2TA (AB103), a CD28 antagonist peptide, prevents inflammatory and thrombotic reactions and protects against gastrointestinal injury in total-body irradiated mice

• Published in: PloS one 2014-07, Vol.9 (7), p.e101161
• Main Authors: Mirzoeva, Salida, Paunesku, Tatjana, Wanzer, M Beau, Shirvan, Anat, Kaempfer, Raymond, Woloschak, Gayle E, Small, Jr, William
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Amino Acid Sequence; Analysis; Animals; Antigens, Differentiation - metabolism; Apoptosis; Biology; Biology and Life Sciences; CD28 antigen; CD28 Antigens - antagonists & inhibitors; CD28 Antigens - chemistry; Cell cycle; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Crypts; Cyclin D1; Cyclin D1 - metabolism; cyclins; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Cytokines; Damage assessment; Drug dosages; Fibrin; Fibrinogen; Fibrinogen - metabolism; Gamma Rays; gastrointestinal tract; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - pathology; Gastrointestinal Tract - radiation effects; Histopathology; HYDRO ENERGY; Immunohistochemistry; Inflammation; Inflammation - etiology; Inflammation - metabolism; Inflammation - prevention & control; Inflammatory response; Injury prevention; Interleukin 6; Interleukin-6 - blood; Irradiated; Irradiation; Jejunum; Jejunum - drug effects; Jejunum - pathology; Jejunum - radiation effects; Laboratory animals; Lymphocytes; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - radiation effects; macrophanges; Male; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Mitigation; Oncology; Peptides; Peptides - pharmacology; Radiation; Radiation damage; Radiation effects; Radiation injuries; Radiation Injuries, Experimental - complications; Radiation-Protective Agents - pharmacology; Rodents; Signaling; Small intestine; small intestines; Thrombosis - blood; Thrombosis - etiology; Thrombosis - prevention & control; Whole-Body Irradiation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0101161

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.