Dendritic cells (DCs) have recently emerged as pivotal players in the development and maintenance of CNS autoimmunity and inflammation. During the previous funding cycle, it was discovered that DC mediated T cell amplification pathways play a critical role in T cell recruitment and function in the CNS. A second major finding was that DCs migrate from the brain to secondary lymphoid organs during CNS inflammation, and this process was critical for the induction and regulation of antigen-specific T cell responses. These discoveries led to novel hypotheses about the role of DCs in the initiation of CNS directed inflammatory responses. The studies proposed in the current application will test the overall hypothesis that DCs are critical for the initiation, regulation, and maintenance of antigen-specific T cell mediated autoimmune responses in the CNS. Specifically, studies proposed in Aim 1 will test the hypothesis that phenotypically and functionally distinct populations of DCs are dynamically recruited to the CNS during chronic progressive experimental autoimmune encephalomyelitis (EAE). These studies will employ a novel method of DC-tracking using magnetic/fluorescent nanobeads to measure the kinetics of DC accumulation in the CNS at various time points following EAE induction. In addition, the role of brain DCs in regulating cellular infiltration into the CNS and the onset of clinical symptoms during CNS autoimmune disease will be determined (Aim 2). Finally, studies proposed in Aim 3 will determine whether CNS DCs sample multiple antigens expressed in oligodendrocytes and amplify antigen-specific immune responses during the initiation and progression of neuro-autoimmune disease. The successful completion of these studies will further define the role of DCs in CNS autoimmune disease and may lead to novel therapeutic strategies for the treatment of inflammatory diseases in the nervous system.

Public Health Relevance

Neuroinflammation in autoimmune and infectious diseases of the central nervous system (CNS) is a result of the activation of the immune system. Recently, CNS dendritic cells (DCs) emerged as pivotal players to regulate this activation process. This present application is designed to understand the pathogenesis of autoimmunity in the CNS and the role of DCs in the initiation and maintenance of CNS inflammatory responses. The outcome of these studies will lead to an improved understanding of the mechanisms of antigen-specific T cell recruitment into the CNS and may provide the foundation for new therapeutic strategies for controlling CNS inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037570-12
Application #
8279438
Study Section
Special Emphasis Panel (ZRG1-BDCN-M (07))
Program Officer
Utz, Ursula
Project Start
2000-02-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
12
Fiscal Year
2012
Total Cost
$318,347
Indirect Cost
$103,972
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Clarkson, Benjamin D; Walker, Alec; Harris, Melissa G et al. (2015) CCR2-dependent dendritic cell accumulation in the central nervous system during early effector experimental autoimmune encephalomyelitis is essential for effector T cell restimulation in situ and disease progression. J Immunol 194:531-41
Harris, Melissa G; Hulseberg, Paul; Ling, Changying et al. (2014) Immune privilege of the CNS is not the consequence of limited antigen sampling. Sci Rep 4:4422
Clarkson, Benjamin D; Walker, Alec; Harris, Melissa et al. (2014) Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE. J Neuroimmunol 277:39-49
Clarkson, Benjamin D S; Ling, Changying; Shi, Yejie et al. (2014) T cell-derived interleukin (IL)-21 promotes brain injury following stroke in mice. J Exp Med 211:595-604
Clarkson, Benjamin D; Héninger, Erika; Harris, Melissa G et al. (2012) Innate-adaptive crosstalk: how dendritic cells shape immune responses in the CNS. Adv Exp Med Biol 946:309-33
Zhu, Bing; Trikudanathan, Subbulaxmi; Zozulya, Alla L et al. (2012) Immune modulation by Lacto-N-fucopentaose III in experimental autoimmune encephalomyelitis. Clin Immunol 142:351-61
Schreiber, Heidi A; Harding, Jeffrey S; Hunt, Oliver et al. (2011) Inflammatory dendritic cells migrate in and out of transplanted chronic mycobacterial granulomas in mice. J Clin Invest 121:3902-13
Lee, JangEun; Sandor, Matyas; Heninger, Erika et al. (2010) Mycobacteria-induced suppression of autoimmunity in the central nervous system. J Neuroimmune Pharmacol 5:210-9
Zozulya, Alla L; Clarkson, Benjamin D; Ortler, Sonja et al. (2010) The role of dendritic cells in CNS autoimmunity. J Mol Med (Berl) 88:535-44
Schreiber, Heidi A; Hulseberg, Paul D; Lee, JangEun et al. (2010) Dendritic cells in chronic mycobacterial granulomas restrict local anti-bacterial T cell response in a murine model. PLoS One 5:e11453

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