Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology.
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.
Larocque
Daniel
D
Gene Therapeutics Research Institute, Cedars-Sinai Biomedical Sciences Graduate Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Sanderson
Nicholas S R
NS
Bergeron
Josée
J
Curtin
James F
JF
Girton
Joe
J
Wibowo
Mia
M
Bondale
Niyati
N
Kroeger
Kurt M
KM
Yang
Jieping
J
Lacayo
Liliana M
LM
Reyes
Kevin C
KC
Farrokhi
Catherine
C
Pechnick
Robert N
RN
Castro
Maria G
MG
Lowenstein
Pedro R
PR
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*
D000276:Adjuvants, Immunologic; D000941:Antigens; D006388:Hemagglutinins; D008024:Ligands; D051941:fms-Like Tyrosine Kinase 3