טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentSchif-Zuck Sagie
SubjectThe Role of Interleukin-18 and Interleukin-18 binding
Protein in T-cell Mediated Autoimmune Diseases
DepartmentDepartment of Medicine
Supervisor Professor Nathan Karin


Abstract

   Experimental autoimmune encephalomyelitis (EAE) is a T cell mediated autoimmune disease of the central nervous system (CNS) that serves as an animal model for human multiple sclerosis (MS). The disease could adoptively transfer by CD4+ T cells selected in response to numerous CNS antigens. Depending on their cytokine profile CD4+ T cells fall into different subsets including: Th1cells that produces large amounts of IFN-g and TNF-a, Th2 cells that mostly produce IL-4, IL-5 and IL-13. Th3 cells, that produce high levels of TGF-b, Tr1 cells that produce high levels of IL-10, and CD4+CD25+ suppressor T cells.  Several groups, including ours, have shown that altering the Th1/Th2 balance towards Th2 suppresses EAE, whereas the direct administration of antigen specific Th2 cells has no beneficial effect on the manifestation of disease. The current study delineates this paradigm. We show that antigen specific Th2 cells, administered during the accelerating phase of disease, preferentially accumulate/propagate at the CNS, but then undergo functional repolarization, and subsequently do not induce spread of tolerance. To determine whether this process is dependent on the inflammatory milieu at the autoimmune site we used a manipulation of targeted cell therapy to over express IL-18 binding protein at this site. This effectively reversed targeted depolarization of Th2 cells, induced infectious spread of T cell tolerance, and suppressed EAE in a disease specific manner. This not only suggests a novel way of targeted cell therapy, but also revisits basic concepts regarding the flexibility of T cell polarization and function in inflammatory autoimmune diseases.