Mechanisms of recovery from experimental allergic encephalomyelitis induced with myelin basic protein peptide 68-86 in Lewis rats: a role for dendritic cells in inducing apoptosis of CD4+ T cells.
Spontaneous remission of experimental allergic encephalomyelitis (EAE) is usually associated with prominent apoptosis. The mechanisms behind apoptosis are unknown. We examined the functions of dendritic cells (DC) from Lewis rats with EAE induced by immunization with myelin basic protein peptide 68-86 (MBP68 - - 86). Recovery from EAE was associated with three major functional changes of freshly prepared DC: (1) elevated proliferation, (2) increased nitric oxide (NO) production, and (3) augmented IFN-gamma secretion. In Freund's complete adjuvant (FCA)-immunized control rats, no increase of proliferation, NO production or IFN-gamma secretion was observed on day 21 post-immunization (p.i.), i.e., recovery from EAE. In vitro effects of IFN-gamma, TNF-alpha, TGF-beta1, IL-4 and IL-10 on DC were examined. IFN-gamma enhanced proliferation and NO production by DC, while TNF-alpha and IL-4 induced only slight DC proliferation. DC from recovering EAE rats (day 21 p.i.) suppressed MBP68 - - 86-induced T cell proliferation compared to DC obtained at other time points in EAE and FCA-immunized rats. DC-derived NO induced apoptosis of CD4+ T cells, thereby inhibiting autoreactive T cell responses. Besides IFN-gamma stimulation, NO production by DC was mainly induced in an antigen-dependent manner when DC were co-cultured with T cells. The results suggest that spontaneous recovery from EAE is associated with augmented DC functions. Overproduction of NO by DC results in apoptosis of autoreactive CD4+ T cells, thereby decreasing autoreactive T cell reactivities. The existence of such a NO negative feedback loop may contribute to remission of EAE.
Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
B G
BG
Xiao
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Huang
L Y
LY
Xu
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Ishikawa
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D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D030161:Avian Proteins; D051940:B7-2 Antigen; D051926:Basigin; D001798:Blood Proteins; D017252:CD3 Complex / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D053938:DNA Fragmentation; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D016130:Immunophenotyping; D016167:Integrin alphaXbeta2 / Q000032:analysis; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D004676:Myelin Basic Protein / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D030161:Avian Proteins; D051940:B7-2 Antigen; D001798:Blood Proteins; C102624:Bsg protein, Gallus gallus; C079432:Bsg protein, rat; D017252:CD3 Complex; C497966:Cd86 protein, rat; D000949:Histocompatibility Antigens Class II; D016167:Integrin alphaXbeta2; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C110235:myelin basic protein 68-86; D016753:Interleukin-10; D051926:Basigin; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma