title: Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology.
abstract: Soluble antigens diffuse out of the brain and can thus stimulate a systemic immune response, whereas particulate antigens (from infectious agents or tumor cells) remain within brain tissue, thus failing to stimulate a systemic immune response. Immune privilege describes how the immune system responds to particulate antigens localized selectively within the brain parenchyma. We believe this immune privilege is caused by the absence of antigen presenting dendritic cells from the brain. We tested the prediction that expression of fms-like tyrosine kinase ligand 3 (Flt3L) in the brain will recruit dendritic cells and induce a systemic immune response against exogenous influenza hemagglutinin in BALB/c mice. Coexpression of Flt3L with HA in the brain parenchyma induced a robust systemic anti-HA immune response, and a small response against myelin basic protein and proteolipid protein epitopes. Depletion of CD4(+)CD25+ regulatory T cells (Tregs) enhanced both responses. To investigate the autoimmune impact of these immune responses, we characterized the neuropathological and behavioral consequences of intraparenchymal injections of Flt3L and HA in BALB/c and C57BL/6 mice. T cell infiltration in the forebrain was time and strain dependent, and increased in animals treated with Flt3L and depleted of Tregs; however, we failed to detect widespread defects in myelination throughout the forebrain or spinal cord. Results of behavioral tests were all normal. These results demonstrate that Flt3L overcomes the brain's immune privilege, and supports the clinical development of Flt3L as an adjuvant to stimulate clinically effective immune responses against brain neo-antigens, for example, those associated with brain tumors.
authors.affiliation: Gene Therapeutics Research Institute, Cedars-Sinai Biomedical Sciences Graduate Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Larocque
authors.forename: Nicholas S R
authors.initials: NS
authors.lastname: Sanderson
authors.forename: Josée
authors.initials: J
authors.lastname: Bergeron
authors.forename: James F
authors.initials: JF
authors.lastname: Curtin
authors.forename: Joe
authors.initials: J
authors.lastname: Girton
authors.forename: Mia
authors.initials: M
authors.lastname: Wibowo
authors.forename: Niyati
authors.initials: N
authors.lastname: Bondale
authors.forename: Kurt M
authors.initials: KM
authors.lastname: Kroeger
authors.forename: Jieping
authors.initials: J
authors.lastname: Yang
authors.forename: Liliana M
authors.initials: LM
authors.lastname: Lacayo
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Reyes
authors.forename: Catherine
authors.initials: C
authors.lastname: Farrokhi
authors.forename: Robert N
authors.initials: RN
authors.lastname: Pechnick
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000941:Antigens / Q000276:immunology; D001921:Brain / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D006388:Hemagglutinins / Q000276:immunology; D007107:Immune System / Q000276:immunology*; D007109:Immunity; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D016548:Prosencephalon / Q000276:immunology; D013116:Spinal Cord / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051941:fms-Like Tyrosine Kinase 3 / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D006388:Hemagglutinins; D008024:Ligands; D051941:fms-Like Tyrosine Kinase 3