title: In vivo treatment with a MHC class I-restricted blocking peptide can prevent virus-induced autoimmune diabetes.
abstract: We tested the in vivo potential of a MHC class I-restricted blocking peptide to sufficiently lower an anti-viral CTL response for preventing virus-induced CTL-mediated autoimmune diabetes (insulin-dependent diabetes mellitus (IDDM)) in vivo without affecting systemic viral clearance. By designing and screening several peptides with high binding affinities to MHC class I H-2Db for best efficiency in blocking killing of target cells by lymphocytic choriomeningitis virus (LCMV) and other viral CTL, we identified the peptide for this study. In vitro, it selectively lowered CTL killing restricted to the Db allele, which correlated directly with the affinity of the respective epitopes. Expression of the blocking peptide in the target cell lowered recognition of all Db-restricted LCMV epitopes. In addition, in vitro expansion of LCMV memory CTL was prevented, resulting in decreased IFN-gamma secretion. In vivo, a 2-wk treatment with this peptide lowered the LCMV Db-restricted CTL response by over threefold without affecting viral clearance. However, the CTL reduction by the peptide treatment was sufficient to prevent LCMV-induced IDDM in rat insulin promoter-LCMV-glycoprotein transgenic mice. Following LCMV infection, these mice develop IDDM, which depends on Db-restricted anti-self (viral) CTL. Precursor numbers of splenic LCMV-CTL in peptide-treated mice were reduced, but their cytokine profile was not altered, indicating that the peptide did not induce regulatory cells. Further, non-LCMV-CTL recognizing the blocking peptide secreted IFN-gamma and did not protect from IDDM. This study demonstrates that in vivo treatment with a MHC class I blocking peptide can prevent autoimmune disease by directly affecting expansion of autoreactive CTL.
authors.affiliation: Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA. matthias@scripps.edu
authors.forename: M G
authors.initials: MG
authors.lastname: von Herrath
authors.forename: B
authors.initials: B
authors.lastname: Coon
authors.forename: H
authors.initials: H
authors.lastname: Lewicki
authors.forename: H
authors.initials: H
authors.lastname: Mazarguil
authors.forename: J E
authors.initials: JE
authors.lastname: Gairin
authors.forename: M B
authors.initials: MB
authors.lastname: Oldstone
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D007156:Immunologic Memory; D007328:Insulin / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008216:Lymphocytic Choriomeningitis / Q000150:complications* / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D019076:Transgenes; D019562:Viral Load
chemical_list: D000956:Antigens, Viral; D000939:Epitopes; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D007328:Insulin; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; C115324:S9M protein, synthetic; D015847:Interleukin-4; D007371:Interferon-gamma