Research

The research in our group aims to characterize pro- and anti-inflammatory mechanisms and biomarkers for Multiple Sclerosis (MS) and other autoimmune diseases.

 

Identification of signaling pathways controlling adaptive and innate immunity. 

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.

 

Aryl Hydrocarbon Receptor (AHR)

AHR controls T cell differentiation in a context-dependent fashion

Role of AHR during the differentiation of Th17 cells

 

 

Role of AHR during the 
differentiation of Tr1 cells

Our Approach

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.

 

Nanoparticle-mediated co-delivery of CNS antigens and ITE

 

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.

 

Serum Antibody Signatures

Antigen Arrays

Antigen Arrays II

 

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.

 

The research in our group is funded by the following agencies:

National Institutes of Health (NIH)
National Multiple Sclerosis Society (NMSS)
Juvenile Diabetes Research Foundation (JDRF)
US-Israel Binational Science Foundation
Harvard Digestive Diseases Center