title: Immune regulatory and neuroprotective properties of preimplantation factor: From newborn to adult.
abstract: Embryonic-maternal interaction from the earliest stages of gestation has a key, sustained role in neurologic development, persisting into adulthood. Early adverse events may be detrimental in adulthood. Protective factors present during gestation could significantly impact post-natal therapy. The role of PreImplantation Factor (PIF) within this context is herein examined. Secreted by viable early embryos, PIF establishes effective embryonic-maternal communication and exerts essential trophic and protective roles by reducing oxidative stress and protein misfolding and by blunting the nocive let-7 microRNA related pathway. PIF's effects on systemic immunity lead to comprehensive immune modulation, not immune suppression. We examine PIF's role in protecting embryos from adverse maternal environment, which can lead to neurological disorders that may only manifest post-nataly: Synthetic PIF successfully translates endogenous PIF features in both pregnant and non-pregnant clinically relevant models. Specifically PIF has neuroprotective effects in neonatal prematurity. In adult relapsing-remitting neuroinflammation, PIF reverses advanced paralysis while promoting neurogenesis. PIF reversed Mycobacterium smegmatis induced brain infection. In graft-vs.-host disease, PIF reduced skin ulceration, liver inflammation and colon ulceration while maintaining beneficial anti-cancer, graft-vs.-leukemia effect. Clinical-grade PIF has high-safety profile even at supraphysiological doses. The FDA awarded Fast-Track designation, and university-sponsored clinical trials for autoimmune disorder are ongoing. Altogether, PIF properties point to its determining regulatory role in immunity, inflammation and transplant acceptance. Specific plans for using PIF for the treatment of complex neurological disorders (ie. traumatic brain injury, progressive paralysis), including neuroprotection from newborn to adult, are presented.
authors.affiliation: The Society for the Investigation of Early Pregnancy (SIEP), Cherry Hill, NJ, USA; BioIncept LLC, Cherry Hill, NJ, USA. Electronic address: barnea@earlypregnancy.org.
authors.forename: E R
authors.initials: ER
authors.lastname: Barnea
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Hospital Ein Kerem, Hebrew University, Jerusalem, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Almogi-Hazan
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Hospital Ein Kerem, Hebrew University, Jerusalem, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Or
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA; Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Catholic University of Sacred Heart, Institute of General Pathology, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ria
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Hospital Ein Kerem, Hebrew University, Jerusalem, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Weiss
authors.affiliation: Yale Women and Children's Center for Blood Disorders, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Paidas
mesh_terms: D000818:Animals; D052818:Autotrophic Processes / Q000502:physiology; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy; D006801:Humans; D007234:Infant, Premature / Q000502:physiology; D007249:Inflammation / Q000188:drug therapy; D009422:Nervous System Diseases / Q000188:drug therapy; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D000066829:Neuroprotection / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism*; D012883:Skin Ulcer / Q000188:drug therapy
chemical_list: D010455:Peptides; D011257:Pregnancy Proteins; C000605122:preimplantation factor, human; C569738:preimplantation factor, synthetic
keywords: Immune regulation; Neuroprotection; PreImplantation Factor (PIF)