title: Single administration of p2TA (AB103), a CD28 antagonist peptide, prevents inflammatory and thrombotic reactions and protects against gastrointestinal injury in total-body irradiated mice.
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.
authors: Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors: Salida
authors: S
authors: Mirzoeva
authors: Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors: Tatjana
authors: T
authors: Paunesku
authors: Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors: M Beau
authors: MB
authors: Wanzer
authors: Atox Bio Ltd, Ness Ziona, Israel.
authors: Anat
authors: A
authors: Shirvan
authors: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors: Raymond
authors: R
authors: Kaempfer
authors: Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors: Gayle E
authors: GE
authors: Woloschak
authors: Department of Radiation Oncology, Loyola University Stritch School of Medicine, Chicago, Illinois, United States of America.
authors: William
authors: W
authors: Small
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D018106:CD28 Antigens / Q000037:antagonists & inhibitors* / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005720:Gamma Rays; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D015850:Interleukin-6 / Q000097:blood; D007583:Jejunum / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D010455:Peptides / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental / Q000150:complications; D011837:Radiation-Protective Agents / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D014916:Whole-Body Irradiation
chemical_list: D000943:Antigens, Differentiation; D018106:CD28 Antigens; D015850:Interleukin-6; D010455:Peptides; D011837:Radiation-Protective Agents; C036763:monocyte-macrophage differentiation antigen; D019938:Cyclin D1; D005340:Fibrinogen; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2