Issazadeh-Navikas Group – University of Copenhagen

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Issazadeh-Navikas Group

Neuroinflammation unit

Our aim is to identify and characterize novel genes and mechanisms essential for neurons in the central nervous system (CNS) to maintain homeostasis, controlling inflammation and cancer of CNS.


Post mitotic neurons are vastly incapable of regeneration. Therefore, it is essential that these indispensable cell types with highly sophisticated functions be protected from inflammatory damage. From an evolutionary standpoint, this is a rather logical explanation for CNS being relatively an immune privileged organ. However, immune cells are infiltrating the CNS, and it is becoming increasingly known that inflammatory cells and mediators are involved in progression of several of neurodegenerative diseases. Neurons have been neglected as cells with major immune regulatory function.

Recently, we have identified two signaling pathways by which neurons are controlling function of inflammatory T cells that are causing CNS inflammation. These two pathways include cytokines and their receptor interactions as well as costimulatory signaling (via receptor-ligand interaction). These important signaling pathways, in addition to many other signaling pathways, are the communicative language of the cells. Any defect in genes and proteins regulating this communication could disturb the tissue homeostasis and result in pathological conditions. 

 

Adapted from Liu et al. Nature Medicine 2006, 12, 518 - 525 .

We are utilizing numerous different experimental approaches to achieve our objectives, including establishment of primary neuronal and T cell cultures and lines, novel gene identification using DNA microarray screen, target gene validation by gene expression, phenotype identification by using small hairpin (sh) RNA to target gene/s of interest, target gene/phenotype validation utilizing several experimental disease models in vivo in wild type versus gene-modified mice, finally validation of target genes and proteins in tissues and cells from human patients. 
There are several extensive projects underway to elucidate novel pathways including some example below.

1.  Identifying additional signaling pathways by which neurons are dictating the fate of inflammatory and regulatory T cells entering CNS and hence terminating CNS inflammation.

 


Adapted from Teige et.al. (2006) J.Immunology 177(6):3542-53. CNS tissue from experimental autoimmune encephalomyelitis, an experimental model for multiple sclerosis. CD1-PE & NKT cells-FITC.

2.  Identifying genes/proteins central for neuronal survival and adequate signaling.

We are utilizing genetic-modified mice and shRNA targeted genes technology to identify genes and signaling pathways essential for neuronal survival in vivo and in vitro. Our extensive work in the area has identified defect in two genes resulting in spontaneous neurodegeneration up to date. 

 

Normal neurons (left) versus gene-defected neurons (right), DAPI-nuclear staining & NF200-FITC.

3.  Identifying novel genes/proteins critical for neurons to maintain CNS homeostasis and control progression of CNS tumors such as glioblastoma multiforme (GBM).

 
Left: CNS tissue with Glioblastoma multiforme (GBM) model. DAPI-nuclear staining showing tumor mass, Beta tubulin-neuronal staining-FITC and GFAP-activated astrocytes-Cy3. Right: Glioblastoma cells expressing costimultory molecules.

Interested postdoctoral scientists, students and lab technicians are always welcomed to contact us regarding possibility to join the group.

Selected recent publications

Liu, Carlsson, Comabella, Wang, Kosicki, Carrion, Hasan, Wu, Montalban, Dziegiel, Sellebjerg, Sørensen, Helin, Issazadeh-Navikas.
FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nat Med. 2014 Feb 16. doi: 10.1038/nm.3485

Liu Y, Teige A, Mondoc E, Ibrahim S, Holmdahl R, Issazadeh-Navikas S.
Endogenous collagen peptide activation of CD1d-restricted NKT cells ameliorates
tissue-specific inflammation in mice. J Clin Invest. 2011 Jan 4;121(1):249-64.

Liu Y, Teige I, Ericsson I, Navikas V, Issazadeh-Navikas S. (2010) Suppression of EAE by oral tolerance is independent of endogenous IFN-beta whereas treatment with recombinant IFN-beta ameliorates EAE. Immunol Cell Biol. 2010 May;88(4):468-76.

Matheu V, Barrios Y, Arnau MR, Navikas V, Issazadeh-Navikas S. (2010) Similar response in male and female B10.RIII mice in a murine model of allergic airway inflammation. Inflamm Res. 2010 Apr;59(4):263-9.  

Teige A, Bockermann R, Hasan M, Olofsson KE, Liu Y, Issazadeh-Navikas S. (2010) CD1d-dependent NKT cells play a protective role in acute and chronic arthritis models by ameliorating antigen-specific Th1 responses. J Immunol. 2010 Jul 1;185(1):345-56.

Liu Y, Teige I, Birnir B, & Issazadeh-Navikas S. (2006). Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nature Medicine 12(5):518-25.

Teige I., Liu Y. & Issazadeh-Navikas S. (2006). IFN-β inhibits T cell activation capacity of CNS potential Antigen Presenting Cells. J Immunol. 177(6):3542-53.

Teige A, Teige I, Lavasani S, Bockermann R, Mondoc E, Holmdahl R, Issazadeh-Navikas S. (2004). CD1-dependent regulation of chronic central nervous system inflammation in experimental autoimmune encephalomyelitis. J. Immunol. 172(1): 186-94.

Teige I, Treschow A, Teige A, Mattsson R, Navikas V, Leanderson T, Holmdahl R, Issazadeh-Navikas S. (2003). IFN-beta Gene Deletion Leads to Augmented and Chronic Demyelinating Experimental Autoimmune Encephalomyelitis.  J. Immunol. 170:4776-84.

Issazadeh S.,  Abdallah K, Chitnis T, Chandraker A, Wells AD, Turka LA, Sayegh MH, Khoury SJ. (2000). Role of passive T-cell death in chronic experimental autoimmune encephalomyelitis. J. Clinical Investigation. 105(8):1109-16.  

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