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Brain-Derived Heat Shock Protein 70-Peptide Complexes Induce NK Cell-Dependent Tolerance to Experimental Autoimmune Encephalomyelitis¹

Grazyna Galazka^*, Mariusz Stasiolek^*, Agata Walczak^*, Anna Jurewicz^*, Alicja Zylicz, Celia F. Brosnan, Cedric S. Raine and Krzysztof W. Selmaj^2,*,

^* Department of Neurology, Medical University of Lodz, Lodz, Poland; Department of Molecular Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland; and Department of Pathology (Neuropathology), Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461

Heat shock proteins (Hsp) are markedly up-regulated at sites of inflammation during autoimmune diseases like experimental autoimmune encephalomyelitis (EAE). In this study, we show that Hsp70-peptide complexes (pc) isolated from brains of mice with EAE prevented the development of EAE clinically and pathologically when administered before proteolipid protein 139–151 (PLP_139–151) immunization. In contrast, pure Hsp70 or Hsp70-pc derived from brains of healthy mice or other inflamed tissue did not modulate the expression of EAE. In animals in which EAE had been suppressed by Hsp70-pc, lymphocytes showed increased cell death in response to PLP_139–151 that correlated with elevated IFN- and NO production. Coculture of spleen cells from Hsp70-pc immunized mice with spleen cells from untreated EAE mice, in addition to depletion experiments, showed that NK cells reduced reactivity to PLP_139–151. Transfer of NK cells from Hsp70-pc-immunized mice to recipients sensitized for EAE abolished disease development. Thus, we propose that Hsp70 demonstrate the ability to bind to peptides generated during brain inflammation and to induce a regulatory NK cell population that is capable of preventing subsequent autoimmunization for EAE.

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