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

• Published in: Journal of Immunology Vol. 176; no. 3; pp. 1588 - 1599
• Main Authors: Galazka, Grazyna, Stasiolek, Mariusz, Walczak, Agata, Jurewicz, Anna, Zylicz, Alicja, Brosnan, Celia F, Raine, Cedric S, Selmaj, Krzysztof W
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.02.2006
• Subjects: Animals; Brain - immunology; Brain - metabolism; Brain - pathology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Proliferation; Cells, Cultured; Coculture Techniques; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Female; HSP70 Heat-Shock Proteins - immunology; HSP70 Heat-Shock Proteins - isolation & purification; HSP70 Heat-Shock Proteins - metabolism; Immune Tolerance; Immunotherapy, Adoptive; Inflammation - immunology; Inflammation - prevention & control; Interferon-gamma - metabolism; Interleukin-10 - biosynthesis; Killer Cells, Natural - immunology; Mice; Mice, Inbred Strains; Myelin Proteolipid Protein - immunology; Nitric Oxide - metabolism; Peptide Fragments - immunology; Peptides - immunology; Peptides - isolation & purification; Peptides - metabolism; T-Lymphocytes - immunology; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.176.3.1588

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 (PLP139-151) 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 PLP139-151 that correlated with elevated IFN-gamma 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 PLP139-151. 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.