Exogenous Fms-Like Tyrosine Kinase 3 Ligand Overrides Brain Immune Privilege and Facilitates Recognition of a Neo-Antigen Without Causing Autoimmune Neuropathology

Authors

Daniel Larocque, David Geffen School of Medicine, California, USA
Nicholas S. R. Sanderson, David Geffen School of Medicine, California, USA
Josée Bergeron, David Geffen School of Medicine, California, USA
James Curtin, Technological University Dublin, IrelandFollow
Joe Girton, David Geffen School of Medicine, California, USA
Mia Wibowo, Cedars-Sinai Biomedical Sciences Graduate Program, Los Angeles, USA
Niyati Bondale, David Geffen School of Medicine, California, USA
Kurt M. Kroeger, David Geffen School of Medicine, California, USA
Jieping Yang, David Geffen School of Medicine, California, USA
Liliana M. Lacayo, Cedars-Sinai Medical Center, Los Angeles, USA
Kevin C. Reyes, Department of PsychiaCedars-Sinai Medical Center, Los Angeles, USA
Catherine Farrokhi, Cedars-Sinai Medical Center, Los Angeles, USA
Robert N. Pechnick, Cedars-Sinai Medical Center, Los Angeles, USA
Maria G. Castro, David Geffen School of Medicine, California, USA
Pedro R. Lowenstein, David Geffen School of Medicine, California, USA

Document Type

Article

Rights

Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

Disciplines

3. MEDICAL AND HEALTH SCIENCES

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.

DOI

https://doi.org/10.1073/pnas.0913496107

Recommended Citation

Larocque, D., Sanderson, N.S.R., & Bergeron, J. (2010). Exogenous Fms-Like Tyrosine Kinase 3 Ligand Overrides Brain Immune Privilege and Facilitates Recognition of a Neo-Antigen Without Causing Autoimmune Neuropathology. Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 32, 14443–14448. doi: 10.1073/pnas.0913496107