PreImplantation factor (PIF) therapy provides comprehensive protection against radiation induced pathologies

// Reut Shainer 1 , Osnat Almogi-Hazan 1 , Arye Berger 1 , Liad Hinden 1 , Martin Mueller 2, 3 , Chaya Brodie 4 , Cedric Simillion 5 , Michael Paidas 2 , Eytan R. Barnea 6, 7, * , Reuven Or 1, * 1 Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel 2 Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA 3 Department of Obstetrics and Gynecology, University Hospital Bern, Bern, 3003, Switzerland 4 Henry Ford Hospital, Detroit, MI 48202, USA 5 Department of Clinical Research, University of Bern, Bern, 3003, Switzerland 6 The Society for The Investigation of Early Pregnancy (SIEP), Cherry Hill, NJ 08003, USA 7 BioIncept, LLC (PreImplantation Factor* Proprietary), Cherry Hill, NJ 08003, USA * These authors contributed equally to this work Correspondence to: Eytan R. Barnea, email: barnea@earlypregnancy.org Keywords: ARS, PreImplantation Factor (PIF), oxidative stress, local & systemic protection Received: May 03, 2016 Accepted: June 30, 2016 Published: July 16, 2016 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.