title: PreImplantation factor (PIF) therapy provides comprehensive protection against radiation induced pathologies.
abstract: Acute Radiation Syndrome (ARS) may lead to cancer and death and has few effective countermeasures. Efficacy of synthetic PIF treatment was demonstrated in preclinical autoimmune and transplantation models. PIF protected against inflammation and mortality following lethal irradiation in allogeneic bone marrow transplant (BMT) model. Herein, we demonstrate that PIF imparts comprehensive local and systemic protection against lethal and sub-lethal ARS in murine models. PIF treatment 2 h after lethal irradiation led to 100% survival and global hematopoietic recovery at 2 weeks after therapy. At 24 h after irradiation PIF restored hematopoiesis in a semi-allogeneic BMT model. PIF-preconditioning provided improved long-term engraftment. The direct effect of PIF on bone marrow cells was also demonstrated in vitro: PIF promoted pre-B cell differentiation and increased immunoregulatory properties of BM-derived mesenchymal stromal cells. PIF treatment also improved hematopoietic recovery and reduced systemic inflammatory cytokine production after sub-lethal radiation exposure. Here, PIF also prevented colonic crypt and basal membrane damage coupled with reduced nitric oxide synthetase (iNOS) and increased (B7h1) expression. Global upper GI gene pathway analysis revealed PIF's involvement in protein-RNA interactions, mitochondrial oxidative pathways, and responses to cellular stress. Some effects may be attributed to PIF's influence on macrophage differentiation and function. PIF demonstrated a regulatory effect on irradiated macrophages and on classically activated M1 macrophages, reducing inflammatory gene expression (iNOS, Cox2), promoting protective (Arg1) gene expression and inducing pro-tolerance cytokine secretion. Notably, synthetic PIF is stable for long-term field use. Overall, clinical investigation of PIF for comprehensive ARS protection is warranted.
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors.forename: Reut
authors.initials: R
authors.lastname: Shainer
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors.forename: Osnat
authors.initials: O
authors.lastname: Almogi-Hazan
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors.forename: Arye
authors.initials: A
authors.lastname: Berger
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors.forename: Liad
authors.initials: L
authors.lastname: Hinden
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.|Department of Obstetrics and Gynecology, University Hospital Bern, Bern, 3003, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Chaya
authors.initials: C
authors.lastname: Brodie
authors.affiliation: Department of Clinical Research, University of Bern, Bern, 3003, Switzerland.
authors.forename: Cedric
authors.initials: C
authors.lastname: Simillion
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Paidas
authors.affiliation: The Society for The Investigation of Early Pregnancy (SIEP), Cherry Hill, NJ 08003, USA.|BioIncept, LLC (PreImplantation Factor* Proprietary), Cherry Hill, NJ 08003, USA.
authors.forename: Eytan R
authors.initials: ER
authors.lastname: Barnea
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors.forename: Reuven
authors.initials: R
authors.lastname: Or
mesh_terms: D054508:Acute Radiation Syndrome / Q000517:prevention & control*; D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006085:Graft Survival; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011509:Proteoglycans / Q000627:therapeutic use*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D011509:Proteoglycans; D011837:Radiation-Protective Agents; C042057:proteolysis-inducing peptide
keywords: ARS; PreImplantation Factor (PIF); local and systemic protection; oxidative stress