Prof. Dr. med. Adriano Fontana

 

Main Goals, Keywords

Pathogenesis of immune mediated diseases of the central nervous system (CNS).
(1) Antigen presenting cells in the brain: a functional characterization of dendritic cells and expression of cytokines (2) interaction of macrophages with neurons (3) host defence in bacterial infections of the CNS.
Keywords: experimental autoimmune encephalitis, demyelination, MHC antigens, CIITA, microglia, dendritic cells, cytokines, meningitis.

Group Members

1 professor, 2 senior research fellows, 2 PhD students, 1 technician

Previous and Current Research

Th1 cytokines are expressed in the CNS in the acute phase of experimental autoimmune encephalitis (EAE) induced by immunization with MOG. Besides cytokines also MHC class II molecules and its regulatory protein CIITA play a crucial role to induction and propagation of EAE. Experiments show the presence of CIITA form I and IV in CNS of mice with EAE. As shown in CIITA form IV gene knockout mice, interferon gamma induces MHC class II in macrophage lineage cells via CIITA form I but not form IV. The latter is required for IFN gamma induced expression of MHC class II in astrocytes and fibroblasts. Interestingly, form CIITA form IV knockout mice have a defect in positive T cell selection and thereby express only very low levels of CD4 T cells (ref. 2 + 3) (collaboration with Prof. W. Reith, University Geneva). Dr. Tobias Suter has recently identified dendritic cells (DC) in the CNS of mice with EAE. His data show that these DCs inhibit T cell activation.

In collaboration with the Department of Neurology at the Klinikum Grosshadern in Munich, Germany, mice having a deletion of the TGFbeta receptor II gene (generated by Dr. Ursula Malipiero) were found to have an improved clearance of S. pneumoniae in the CNS. Thereby, these mice show less secondary brain damage in the meningitis model investigated.ge in the meningitis model investigated.

Future Projects

In future studies special attention will be given to the role of dendritic cells in the onset and course of EAE. Functional characterization of these DCs is currently in process.rrently in process.

Investigations are going on to understand the influence of TGFbeta on leukocyte function in bacterial meningitis.

Techniques and Equipment

The EAE model is well established using active immunization and T cell transfer. Molecular and immunhistological methods to express and detect cytokines in the CNS (transgeneic mice, in-situ hybridization, RNase protection assays and Western blot). Various functional assays for cytokines and for the function and characterization of antigen presenting cells.tion of antigen presenting cells.

Selected Publications

• Recher M, Malipiero U, Schaer DJ, Koedel U, Pfister HW, Birchler T, Petrausch U, Claus H, Gast H, Fontana A. Inhibition of meningitis-associated neutrophil apoptosis by TNF-α depends on functional PI3-kinase in monocytes. J Leukoc Biol. 2013 Feb;93(2):259-66. doi: 10.1189/jlb.0511218. Epub 2012 Nov 8.
• Gast H, Müller A, Lopez M, Meier D, Huber R, Dechent F, Prinz M, Emmenegger Y, Franken P, Birchler T, Fontana A. CD40 activation induces NREM sleep and modulates genes associated with sleep homeostasis. Brain Behav Immun. 2013 Jan;27(1):133-44. doi: 10.1016/j.bbi.2012.10.004. Epub 2012 Oct 13.
• Gast H, Gordic S, Petrzilka S, Lopez M, Müller A, Gietl A, Hock C, Birchler T, Fontana A. Transforming growth factor-beta inhibits the expression of clock genes. Ann N Y Acad Sci. 2012 Jul;1261(1):79-87. doi: 10.1111/j.1749-6632.2012.06640.x

Funding

Swiss National Science Foundation (including NCCR), Swiss Society for Multiple Sclerosis, Gianni Rubatto Stiftung

URL

http://www.klimm.usz.ch/LehreUndForschung/Seiten/Mitarbeitende.aspx