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Francisco Javier Quintana, PhD
Associate Scientist, Brigham and Women's Hospital
Professor of Neurology, Harvard Medical School

Brigham and Women's Hospital
Department of Neurology
75 Francis Street
Boston, MA 02115

Research Location: Harvard Institute of Medicine

Phone: 617-525-5317
Email: fquintana@rics.bwh.harvard.edu

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Research Narrative:

The research in our group aims to characterize molecular mechanisms that control the activity of the immune system, with the ultimate goal of identifying novel therapeutic targets and biomarkers for immune-mediated disorders.

Identification of signaling pathways involved in immune tolerance.  C. elegans and D. melanogaster are useful models to study innate immunity, but they lack an adaptive immune system where to study immunoregulatory mechanisms relevant to MS and other autoimmune diseases. To identify signaling pathways that control the immune response in vertebrates we studied the potential for adaptive autoimmunity and immunoregulation in the zebrafish. Using zebrafish antigen microarrays we found that neuroinflammation can be induced in zebrafish upon immunization with autologous CNS. Moreover, we found in zebrafish immunoregulatory mechanisms similar to those that regulate immunity in mice and humans. Our findings on zebrafish immunity led us to identify the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of the differentiation of zebrafish, murine and human regulatory T cells and pathogenic T cells. Thus, AHR is a potential target for the treatment of autoimmune diseases, and the zebrafish is a new model to identify targets and drug candidates for the modulation of the immune response.  We have recently generated new reporter zebrafish lines to study innate and the adaptive immunity in zebrafish experimental models of central nervous system and peripheral inflammation.

Nanoparticles for the induction of antigen-specific tolerance.  Ligand-activated transcription factors are potential targets for immunotherapy, however the therapeutic targeting of AHR requires the identification of non-toxic ligands that trigger its immunomodulatory activities.  In addition, since AHR is expressed by several cell-types, it is important to develop methods for the activation of AHR in a cell-specific manner.  We have found that an endogenous AHR ligand present in mucosal surfaces can promote the differentiation of Tregs and tolerogenic dendritic cells. To facilitate the delivery of AHR-ligands in a cell-specific manner, we have developed gold-based nanoparticles loaded with AHR ligands and antigens, and coated with cell-targeting monoclonal antibodies.  The therapeutic efficacy of these nanoparticles is being evaluated in different experimental paradigms. We are also studying the use of other nanoparticle-based approaches for the modulation of autoimmunity-related immune mechanisms.

Biomarkers for patient stratification and monitoring.  We have developed antigen arrays to study the immune response in MS and other immune-mediated disorders. Using antigen microarrays we found patterns of serum autoantibodies that distinguish MS from healthy controls and other neurologic or autoimmune diseases. We also found unique antibody patterns linked to clinical types or stages of MS, or to disease pathology as determined by biopsy. These serum immune signatures provide a new tool for the individualized management of the disease.  We are currently investigating the association of antibody patterns, as detected with antigen arrays, with magnetic resonance imaging (MRI) measures of disease progression, genetic determinants of disease and the response to specific therapeutic agents. 

Characterization of new pathologic processes. We have developed reverse protein microarrays to identify signaling pathways that participate in MS pathogenesis and progression. MS begins as a relapsing-remitting disease (RRMS) that is followed by a progressive phase (SPMS). Although the progressive phase causes the greatest disability and has no effective therapy, the processes that drive SPMS are mostly unknown. Using reverse protein arrays we identified a signaling pathway that promotes the chronic activation of the CNS innate immune response through a mechanism mediated by the Toll-like Receptor 2 (TLR2) and poly-ADP polymerase-1 (PARP1).  PARP1 can also be activated by microbial TLR ligands, uncovering a new link for innate immunity and microbes in MS and identifying the TLR2/PARP1 axis as a potential target for therapy for SPMS.  We are using a new experimental model of SPMS to characterize the cross-talk between the adaptive and the innate immune response in the CNS during SPMS.


Education:
The Weizmann Institute of Science, 2003, PhD
PhD

Lab Members:
Ruxandra Covacu, Research Fellow
Evan Burns, Research Technician
Meghan Nadeau, Research Technician
Chun-Cheih Chao, Research Fellow
Ivan Mascanfroni, Research Fellow
Ada Yeste, Graduate Student
Sharmila Sambanthamoorthy, Research Technician
Bonny Pattel, Research Specialist
Keith Kallas, Research Technician

Publications (Pulled from Harvard Catalyst Profiles):

1. Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol. 2019 Mar; 19(3):184-197.

2. Wheeler MA, Jaronen M, Covacu R, Zandee SEJ, Scalisi G, Rothhammer V, Tjon EC, Chao CC, Kenison JE, Blain M, Rao VTS, Hewson P, Barroso A, Gutiérrez-Vázquez C, Prat A, Antel JP, Hauser R, Quintana FJ. Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation. Cell. 2019 Jan 24; 176(3):581-596.e18.

3. Starossom SC, Campo Garcia J, Woelfle T, Romero-Suarez S, Olah M, Watanabe F, Cao L, Yeste A, Tukker JJ, Quintana FJ, Imitola J, Witzel F, Schmitz D, Morkel M, Paul F, Infante-Duarte C, Khoury SJ. Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation. Nat Commun. 2019 01 15; 10(1):217.

4. Wheeler MA, Quintana FJ. Regulation of Astrocyte Functions in Multiple Sclerosis. Cold Spring Harb Perspect Med. 2019 Jan 02; 9(1).

5. Quintana FJ. Astrocytes play a crucial role in the formation and evolution of MS lesions - Commentary. Mult Scler. 2019 Jan; 25(1):19-20.

6. Xie A, Robles RJ, Mukherjee S, Zhang H, Feldbrügge L, Csizmadia E, Wu Y, Enjyoji K, Moss AC, Otterbein LE, Quintana FJ, Robson SC, Longhi MS. HIF-1a-induced xenobiotic transporters promote Th17 responses in Crohn's disease. J Autoimmun. 2018 Nov; 94:122-133.

7. Dossi DE, Chaves H, Heck ES, Rodriguez Murúa S, Ventrice F, Bakshi R, Quintana FJ, Correale J, Farez MF. Effects of Systolic Blood Pressure on Brain Integrity in Multiple Sclerosis. Front Neurol. 2018; 9:487.

8. Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC, Ardura-Fabregat A, de Lima KA, Gutiérrez-Vázquez C, Hewson P, Staszewski O, Blain M, Healy L, Neziraj T, Borio M, Wheeler M, Dragin LL, Laplaud DA, Antel J, Alvarez JI, Prinz M, Quintana FJ. Microglial control of astrocytes in response to microbial metabolites. Nature. 2018 05; 557(7707):724-728.

9. Rothhammer V, Borucki DM, Kenison JE, Hewson P, Wang Z, Bakshi R, Sherr DH, Quintana FJ. Detection of aryl hydrocarbon receptor agonists in human samples. Sci Rep. 2018 Mar 21; 8(1):4970.

10. Dolciami D, Gargaro M, Cerra B, Scalisi G, Bagnoli L, Servillo G, Fazia MAD, Puccetti P, Quintana FJ, Fallarino F, Macchiarulo A. Binding Mode and Structure-Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist. ChemMedChem. 2018 02 06; 13(3):270-279.