title: Time limited immunomodulatory functions of transplanted neural precursor cells.
abstract: Fetal neural stem/precursor cells (NPCs) possess powerful immunomodulatory properties which enable them to protect the brain from immune-mediated injury. A major issue in developing neural stem/precursor cell (NPC) therapy for chronic neuroinflammatory disorders such as multiple sclerosis is whether cells maintain their immune-regulatory properties for prolonged periods of time. Therefore, we studied time-associated changes in NPC immunomodulatory properties. We examined whether intracerebrally-transplanted NPCs are able to inhibit early versus delayed induction of autoimmune brain inflammation and whether allogeneic NPC grafts continuously inhibit host rejection responses. In two experimental designs, intraventricular fetal NPC grafts attenuated clinically and pathologically brain inflammation during early EAE relapse but failed to inhibit the disease relapse if induced at a delayed time point. In correlation, long-term cultured neural precursors lost their capacity to inhibit immune cell proliferation in vitro. Loss of NPC immune functions was associated with transition into a quiescent undifferentiated state. Also, allogeneic fetal NPC grafts elicited a strong immune reaction of T cell and microglial infiltration and were rejected from the host brain. We conclude that long-term functional changes in transplanted neural precursor cells lead to loss of their therapeutic immune-regulatory properties, and render allogeneic grafts vulnerable to immunologic rejection. Thus, the immunomodulatory effects of neural precursor cell transplantation are limited in time.
authors.affiliation: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center Jerusalem, Israel.
authors.forename: Nina
authors.initials: N
authors.lastname: Fainstein
authors.forename: Ofira
authors.initials: O
authors.lastname: Einstein
authors.forename: Mikhal E
authors.initials: ME
authors.lastname: Cohen
authors.forename: Livnat
authors.initials: L
authors.lastname: Brill
authors.forename: Iris
authors.initials: I
authors.lastname: Lavon
authors.forename: Tamir
authors.initials: T
authors.lastname: Ben-Hur
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D049109:Cell Proliferation; D003342:Corpus Striatum / Q000503:physiopathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004660:Encephalitis / Q000209:etiology / Q000517:prevention & control*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000601:surgery*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D008214:Lymphocytes / Q000502:physiology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D058953:Neural Stem Cells / Q000276:immunology*; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000209:etiology / Q000473:pathology / Q000601:surgery*; D016627:Oxidopamine / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity; D011247:Pregnancy; D033581:Stem Cell Transplantation / Q000379:methods*; D013997:Time Factors
chemical_list: D018663:Adrenergic Agents; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D049452:Green Fluorescent Proteins; D007371:Interferon-gamma; D016627:Oxidopamine