T helper (Th)17 is a recently identified subset of IL-17-producing CD4+ cells that are potent inducers of tissue inflammation and have been associated with many experimental autoimmune diseases and human inflammatory conditions. In mice, Th17 cells induce the experimental allergic encephalomielitic (EAE), the murine model of multiple sclerosis (MS), a T-cell-dependent autoimmune disease that affects the central nervous system (CNS). We have recently demonstrated that peripheral blood Th17 cells are expanded in the active phase of MS (AMS). They express higher level of IFNAR1 cells and are more susceptible to apoptotic effect mediated by IFNa/b. These data strongly suggest that the increase of Th17 might be involved in relapsing of MS and explain one of the possible mechanisms of action of the therapeutic effect of IFNb in SM. Further data have indicated that during the development of human Th17, the transient up-regulation of the IFNgR2 chain renders these cells susceptible to the suppressive effect of IFNg and that the sensitivity to the apoptotic effect of IFNg of PB Th17 from MS patients could be reinstated via stimulation with anti-CD3 mAb.In this project we will carry out studies aimed to characterize Th17 lymphocytes in relapsing-remitting multiple sclerosis (RR-MS) and investigate the role of IFNs/STAT1 in their development and inactivation.The accomplishment of this research program will clarify the pathogenic role of Th17 in MS and some of the still unknown effects of the IFNb-based therapy in MS, and will be of assistance for a more rational administration of this drug in MS.
ascertain whether the inhibitory effect of IFNa/b on Th17 cells is due either to a direct apoptotic effect, or to an indirect effect mediated by antigen-presenting cells that in turn secrete suppressive cytokines (e.g. IL-27).
provide information on how the up-regulation of IFNg/STAT1 signaling through the modulation of IFNg receptor would inhibit the development of Th17 lymphocytes.
The ability of Th17 cells from SM patients to react to the self-antigen myelin basic protein and their TCR beta chain rearrangement will be analyzed by Elispot and Spectrtyping methodolies respectively. The ability of Th17 to release or express other Th17-related cytokines (e.g. IL-22, RORgT, CD161, CCR4, CCR6) will be investigated in a large cohort of MS patients by cytofluorimetry. The way to inhibit Th17 expansion through the modulation of the IFN/STAT1 signaling pathway will be investigated. Experiments aimed to perturb the expression of IFN receptors on developing Th17 cells by using a pharmacological modulator of the IFNg receptor or a lentivirus expressing mutated IFN receptors will be performed. Finally, studies will be conducted on MS peripheral blood lymphocytes to understand the mechanisms by which IFNs directly or indirectly inhibit (via antigen presenting cells) the Th17 response.
Characterization of pathogenic Th subsets in multiple sclerosis
Understand the mechanisms of action of IFNs in multiple sclerosis
Develop immunotherapeutic and vaccination strategies for the treatment of pancreatic cancer.
Proteomics, pancreatic cancer, vaccination, immunotherapy, autoantibodies, early diagnosis, genetically