title: Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes.
abstract: The self-reactive CD4 T-cells play an essential role in triggering and sustaining organ-specific autoimmune diseases. Silencing or elimination of these cells can prevent and reverse an autoimmune process. We have previously showed that a single dose-administration of a soluble dimeric MHC II-peptide chimera (DEF) in double-transgenic mice delayed the onset autoimmune diabetes, and restored the euglycemia in already diabetic mice for a period of 1 week. DEF dimer protection relied on induction of anergy of diabetogenic CD4 T-cells in spleen, and stimulation of IL-10-secreting T regulatory type 1 cells in pancreas. Herein, we show that an octameric form of DEF has doubled the period of protection and reversal of disease by clonal deletion of diabetogenic CD4 T-cells in both the thymic and peripheral compartments. Deletion occurred by activation-induced cell death subsequent to repartitioning and signaling of FAS-FADD apoptotic module in the plasma membrane lipid rafts. Our previous and present data indicated first, that DEF valence translates into various effects on the antigen-specific CD4 T-cells, i.e., Th2 immune deviation, anergy, and apoptosis. Second, the present findings argue for a better efficacy of clonal deletion than anergy of diabetogenic CD4 T-cells for the protection and reversal of autoimmune diabetes.
authors: Department of Medicine, Division of Immunology, Uniformed Services University of Health Sciences, 4301, Jones Bridge Road, Bethesda, MD 20814, USA.
authors: Anca
authors: A
authors: Preda-Pais
authors: Alexandru C
authors: AC
authors: Stan
authors: Sofia
authors: S
authors: Casares
authors: Constantin
authors: C
authors: Bona
authors: Teodor-D
authors: TD
authors: Brumeanu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D017637:Clonal Deletion / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000627:therapeutic use; D021962:Membrane Microdomains / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000627:therapeutic use; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D015398:Signal Transduction / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D000949:Histocompatibility Antigens Class II; D010455:Peptides; D011993:Recombinant Fusion Proteins