Multiple sclerosis (MS) is caused by an uncontrolled immune response against self-antigens in the central nervous system. The autoreactive components in the immune system are usually controlled by regulatory T cells (T{reg}). Not surprisingly, deficits in the T{reg} compartment are associated to MS and the susceptibility of mice to develop experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Thus, the study of the molecular mechanisms controlling T{reg} differentiation is needed to understand MS pathology and identify new therapeutic targets;these studies, however, cannot be easily performed in mammals. Worms and flies have been useful in the identification of the mechanisms governing innate immunity, but invertebrates do not have T{reg}. We found that the zebrafish has an immune system that shares several features with its mammalian counterpart, including the genes driving T{reg} differentiation. In this application we will use mice and zebrafish to identify the molecular pathways that control T{reg} generation. This goal will be achieved by three independent approaches: 1. Bioinformatic identification of transcription factors controlling T{reg} differentiation. 2. High throughput screen to identify chemicals that regulate T{reg} differentiation. 3. Characterization of the role of the transcription factors and chemical compounds on T{reg} activity during the course of EAE. This project has the potential to identify therapeutic targets for the management of MS, and to establish the zebrafish as a platform for the high throughput identification of immunomodulatory drugs. In summary, this is an innovative project that will combine the experimental advantages offered by mice and zebrafish to identify pathways controlling T{reg} generation and is consistent with the aims of the New Pathway to Independence Award Program.

Public Health Relevance

Studying the mechanisms that control immunoregulation is necessary to understand and identify new therapies for autoimmune disorders but these studies are not easily performed in mammals. We have found that immunoregulatory mechanisms similar to those found in mammals operate in the zebrafish. In this application we propose to perform investigations in mice and zebrafish (Danio rerio) as a model useful for the identification of compounds and signaling pathways that regulate the immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Transition Award (R00)
Project #
4R00AI075285-02
Application #
8109613
Study Section
Special Emphasis Panel (NSS)
Program Officer
Prograis, Lawrence J
Project Start
2010-09-15
Project End
2012-08-31
Budget Start
2010-09-15
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$254,850
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Covacu, Ruxandra; Philip, Hagit; Jaronen, Merja et al. (2016) System-wide Analysis of the T Cell Response. Cell Rep 14:2733-44
Goettel, Jeremy A; Gandhi, Roopali; Kenison, Jessica E et al. (2016) AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice. Cell Rep 17:1318-1329
Rothhammer, Veit; Mascanfroni, Ivan D; Bunse, Lukas et al. (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22:586-97
Joller, Nicole; Lozano, Ester; Burkett, Patrick R et al. (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40:569-81
Mayo, Lior; Trauger, Sunia A; Blain, Manon et al. (2014) Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med 20:1147-56
Quintana, Francisco J (2013) Regulation of central nervous system autoimmunity by the aryl hydrocarbon receptor. Semin Immunopathol 35:627-35
Quintana, Francisco J; Yeste, Ada; Weiner, Howard L et al. (2012) Lipids and lipid-reactive antibodies as biomarkers for multiple sclerosis. J Neuroimmunol 248:53-7
Lee, Youjin; Awasthi, Amit; Yosef, Nir et al. (2012) Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13:991-9
Liu, Sue M; Sutherland, Andrew P R; Zhang, Zheng et al. (2012) Overexpression of the Ctla-4 isoform lacking exons 2 and 3 causes autoimmunity. J Immunol 188:155-62
Quintana, Francisco J; Jin, Hulin; Burns, Evan J et al. (2012) Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat Immunol 13:770-7

Showing the most recent 10 out of 14 publications