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Targeted Overexpression of IL-18 Binding Protein at the Central Nervous System Overrides Flexibility in Functional Polarization of Antigen-Specific Th2 Cells¹

Sagie Schif-Zuck^*, Juergen Westermann, Nir Netzer^*, Yaniv Zohar^*, Moran Meiron^*, Gizi Wildbaum^* and Nathan Karin^2,*,

^* Department of Immunology and Rappaport Family Institute for Research in the Medical Sciences, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; and Institute of Anatomy, University of Luebeck, Luebeck, Germany

The current study shows that functional polarization of Ag-specific CD4⁺ Th2 cells entering the CNS during the accelerating phase of experimental autoimmune encephalomyelitis is flexible and dependent on the cytokine milieu there. Thus, targeted cell/gene therapy by Ag-specific T cells overexpressing IL-18 binding protein overrides this flexibility and induces infectious spread of T cell tolerance. Using a congenic system, we demonstrated that at this time, Ag-specific Th2 cells accumulate at the CNS but then arrest of IL-4 production. A manipulation of targeted cell/gene delivery was then used to detect whether this function is dependent on the cytokine milieu there. Targeted overexpression of IL-18 binding protein, a natural inhibitor of IL-18, restored the ability of these Ag-specific Th2 cells to produce IL-4 and subsequently induce protective spread of Th2 polarization. These findings not only suggest a novel way of therapy, but also explain why shifting the balance of Ag-specific T cells toward Th2 suppresses ongoing experimental autoimmune encephalomyelitis, whereas a direct transfer of these cells is ineffective.

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