Abstract
Introduction
Embryo-derived PIF modulates systemic maternal immunity without suppression. Synthetic
analog (sPIF) prevents juvenile diabetes, preserves islet function, reducing oxidative
stress/protein misfolding. We investigate sPIF effectiveness in controlling neuroinflammation/MS.
Methods
Examine sPIF-induced protection against harsh, clinical-relevant murine EAE-PLP acute
and chronic models. Evaluate clinical indices: circulating cytokines, spinal cord
histology, genome, canonical global proteome, cultured PLP-activated splenocytes cytokines,
and immunophenotype.
Results
Short-term, low-dose sPIF prevented paralysis development and lowered mortality (P<0.05). Episodic sPIF reversed chronic paralysis (P<0.0001) completely in >50%, by day 82. Prevention model: 12 days post-therapy, sPIF reduced circulating IL12 ten-fold and inflammatory cells access
to spinal cord. Regression model: sPIF blocked PLP-induced IL17 and IL6 secretions.
Long-term chronic model: sPIF reduced spinal cord pro-inflammatory cytokines/chemokines,
(ALCAM, CF1, CCL8), apoptosis-promoters, inflammatory cells access (JAM3, OPA1), solute
channels (ATPases), aberrant coagulation factors (Serpins), and pro-antigenic MOG.
Canonical proteomic analysis demonstrated reduced oxidative phosphorylation, vesicle
traffic, cytoskeleton remodeling involved in neuro-cytoskeleton breakdown (tubulins),
associated with axon re-assembly by (MTAPs)/improved synaptic transmission.
Conclusion
sPIF – through coordinated central and systemic multi-targeted action – reverses neuroinflammation/MS
and imparts significant neuroprotective effects up to total paralysis resolution.
Clinical testing is warranted and planned.
Keywords
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References
- Immunology of multiple sclerosis.Annu Rev Immunol. 2005; 23: 683-747
- Multiple sclerosis.J Clin Invest. 2004; 113: 788-794
- Mycobacterium smegmatis expressing a chimeric protein MPT64-proteolipid protein (PLP) 139–151 reorganizes the PLP-specific T cell repertoire favoring a CD8-mediated response and induces a relapsing experimental autoimmune encephalomyelitis.J Immunol. Jan. 1 2010; 184 (Epub 2009 Nov 30): 222-235
- Expression profiling identifies responder and non-responder phenotypes to interferon-beta in multiple sclerosis.Brain. 2003; 126: 1419-1429
- Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of phase III multicenter, double-blind placebo-controlled trial.Neurology. 1995; 45: 1268-1276
- International Natalizumab Multiple Sclerosis Trial Group. A controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med. 2003; 348: 15-23
- Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores.Blood. 2003; 102: 2373-2378
- Pregnancy is associated with a lower risk of onset and better prognosis in multiple sclerosis.Brain. 1995; 188: 253-261
- Manifestations of chronic disease during pregnancy.JAMA. 2005; 21 (2751–57.36)
- Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis.Neurology. 1998; 52: 1230-1238
- Amelioration of autoimmune neuroinflammation by recombinant human alphafetoprotein.Exp Neurol. 2006; 198: 136-144
- A protective effect of early pregnancy factor on experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein.J Neurol Sci. 2003; 216: 33-41
- Inhibition of acute, experimental autoimmune encephalomyelitis by the synthetic immunomodulator linomide.Ann Neurol. 1993; 34: 654-660
- Modeling multiple sclerosis in laboratory animals.Semin Immunopathol. 2009; 31: 479-495https://doi.org/10.1007/s00281-009-0181-4
- Multiple mechanisms of peripheral T cell tolerance to the fetal-allograft.J Immunol. 1998; 160: 3086-3090
- The immunological paradox of pregnancy: a reappraisal.Placenta. 2004; 25: 1-8
- Use of lymphocyte platelet binding assay for detecting a pre-implantation factor: a quantitative assay.Am J Reprod Immunol. 1994; 32: 133-138
- Embryonic origin of preimplantation factor (PIF): biological activity and partial characterization.Mol Hum Reprod. 1996; 2: 883-887
- Pre-implantation factor (PIF) predicts subsequent pregnancy loss.Am J Reprod Immunol. 1995; 34: 88-92
- Progress in characterization of pre-implantation factor (PIF) in embryo cultures and in vivo.J Reprod Immunol. 1999; 42: 95-99
- Assays for preimplantation factor and preimplantation factor peptides. United States patent no. US7,273,708 B2. Sep. 25 2007
- Insight into early pregnancy events: the emerging role of the embryo.Am J Reprod Immunol. 2004; 51: 319-322
- Signaling between embryo and mother in early pregnancy: basis for development of tolerance.in: Carp H. Recurrent pregnancy loss. Taylor & Francis, 2007: 15-23
- PreImplantation Factor (PIF*) correlates with early mammalian embryo development—bovine and murine models.Reprod Biol Endocrinol J. 2011; 9: 63-73
- PreImplantation Factor negates embryo toxicity and promotes embryo development in culture.Reprod Biomed Online. 2011; https://doi.org/10.1016/j.rbmo.2011.06.009
- Genomic and proteomic investigation of preimplantation factor's impact on human decidual cells.Am J Obstet Gynecol. 2010; 202: 459.e1-459.e8
- Preimplantation factor promotes first trimester trophoblast invasion.Am J Obstet Gynecol. 2010; 203 (Epub 2010 Aug 12): 402.e1-402.e4
- Applying embryo-derived immune tolerance to the treatment of immune disorders.Ann N Y Acad Sci. 2007; 1110: 602-618
E.R. Barnea, S. Ramu, PIF modulated gene expression in human Peripheral Blood Mononuclear Cell (PBMCs) GSE18291[Accession]. NCBI, GeoDatasets.
- PreImplantation Factor (PIF) analog prevents type I diabetes mellitus (TIDM) development by preserving pancreatic function in NOD mice.Endocrine. Mar. 22 2011; (Epub)
- Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody.J Immunol. 2005; 175: 4761-4768
- Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress.Brain. 2006; 129 (Epub 2006 Feb 27): 1306-1318
- Alterations of transcriptomic networks in adoptive transfer experimental autoimmune encephalomyelitis.Front Integ Neurosci. 2007; 1: 1-17
- IL-6 transsignalling modulates the early effector phase of EAE and targets the blood–brain barrier.J Neuroimmunol. 2008; 205: 64-72
- Induction and effector functions of T(H)17 cells.Nature. Jun. 19 2008; 453: 1051-1057
- CD4 T cells mediate axonal damage and spinal cord motor neuron apoptosis in murine PO106-125-induced experimental autoimmune neuritis.Am J Pathol. Jul. 2008; 173 (Epub 2008 Jun 5): 93-105
- Interleukin-1: a master regulator of neuroinflammation.J Neurosci Res. 2004; 78: 151-156
- Negative regulation of Toll-like receptor-mediated signaling by Tollip.J Biol Chem. 2002; 277: 7059-7065
- IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis.J Immunol. 2006; 177: 566-573
- MIF signal transduction initiated by binding to CD74.J Exp Med. 2003; 197: 1467-1476
- The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE).Semin Immunol. 2003; 15 (Review): 23-32
- Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system.Nat Immunol. 2003; 8: 137-145
F.A. Loucks, Caspases indirectly regulate cleavage of the mitochondrial fusion GTPase OPA1 in neurons undergoing apoptosis Brain Res Brain Res 2009 Jan 23;1250:63–74 2008;Nov 18. [Epub ahead of print].
- Suppression of celltransferred experimental autoimmune encephalomyelitis in defibrinated Lewis rats.J Neuroimmunol. 1996; 71: 131-137
- Thrombin in inflammatory brain diseases.Autoimmunity. 2006; (Rev. 5, 528-31-38)
- Blockade of Ca2+-activated K+ channels in T cells: an option for the treatment of multiple sclerosis?.Eur J Immunol. 2005; 35: 1023-1026
- Blocking ion channel KCNN4 alleviates the symptoms of experimental autoimmune encephalomyelitis in mice.Eur J Immunol. 2005; 35: 1027-1036
- Heightened intrathecal release of axonal cytoskeletal proteins in multiple sclerosis is associated with progressive disease and clinical disability.J Neuroimmunol. 2002; 122: 132-139
- Tubulin transport in neurons.J Cell Biol. 1996; 133: 1355-1366
- Expression of ionotropic glutamate receptor GLUR3 and effects of glutamate on MBP- and MOG-specific lymphocyte activation and chemotactic migration in multiple sclerosis patients.J Neuroimmunol. Aug. 2007; 188 (Epub 2007 Jul 12): 146-158
- Abundant extracellular myelin in the meninges of patients with multiple sclerosis.Neuropathol Appl Neurobiol. Jun. 2009; 35 (Epub 2008 Sept 17): 283-295
- The cell adhesion molecule neuroplastin-65 inhibits hippocampal long-term potentiation via a mitogen-activated protein kinase p38-dependent reduction in surface expression of GluR1-containing glutamate receptors.J Neurochem. 2006; 9: 850-860
- Rabphilin-3A: a multifunctional regulator of synaptic vesicle traffic.J Gen Physiol. 1998; 111: 243-245
- Crosstalk between Cdk5 and GSK3beta: implications for Alzheimer's disease.Front Mol Neurosci. 2009; 2 (Epub 2009 May 29): 2
- Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation.Hum Mol Genet. 2009; 18 (Epub 2009 Apr 28): 2575-2583
Article info
Publication history
Published online: October 14, 2011
Accepted:
July 28,
2011
Received in revised form:
July 26,
2011
Received:
June 28,
2011
Footnotes
☆PIF* proprietary.
Identification
Copyright
© 2011 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
