Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Self-reactive T cell activation and innate immune cell activation are thought to be major eliciting factors for the appearance of the symptomatology associated with the damage of the myelin sheath. Evidences exist that point out to reactivation of memory T cells and/or epitope spreading (i.e. neoautoreactivity) to explain the chronicity and the relapsing-remitting clinical course often associated with the disease. The study of MS has advanced dramatically with the use of different rodent models, including rats and mice. The animals present with relapsing episodes that are at least partially due to epitope spreading, which gives rise to the activation of new CD4+ T cells recognizing other CNS peptides. Experiments carried out in the murine model have indicated that neoreactive CD4+ T cells are able to induce relapsing episodes. Therefore, the control of these relapsing episodes would provide a means to evade progression of disease. We propose that the inhibition of T cell activation in response to relapsing-associated epitopes during remission of the acute phase of the disease will prevent the appearance of relapsing episodes. Peptide specific disease therapy is difficult due to the diversity of peptides that can trigger relapsing episodes in humans. Alternative approaches include the inhibition of T cell activation using blocking antibodies to costimulatory molecules. We propose to use a T cell specific activation inhibitor as a potential viable alternative for treatment of patients with MS. We have cloned a protein from tick saliva (Salp15) that inhibits CD4+ T cell activation during encounter with the antigen, by preventing the production of the autocrine growth factor interleukin 2. Salp15 inhibits TCR-mediated Ca2+ fluxes that lead to impaired activity of the transcription factor NF-AT, without affecting the activation of effector T cells. This protein is a promising tool for the generation of immunotherapies aimed at the prevention of relapsing of MS.
| Juncadella, Ignacio J; Bates, Tonya C; Suleiman, Reem et al. (2010) The tick saliva immunosuppressor, Salp15, contributes to Th17-induced pathology during Experimental Autoimmune Encephalomyelitis. Biochem Biophys Res Commun 402:105-9 |
