Cellular mRNA expression of interferon-gamma (IFN-gamma), IL-4 and transforming growth factor-beta (TGF-beta) in rats nasally tolerized against experimental autoimmune myasthenia gravis (EAMG).
Nasal administration of nicotinic acetylcholine receptor (AChR) to Lewis rats prior to myasthenogenic immunization with AChR plus Freund's complete adjuvant (FCA) resulted in prevention or marked decrease of the severity of EAMG, suppression of AChR-specific B cell responses and of AChR-reactive T cell functions. To examine the involvement of immunoregulatory cytokines and the underlying mechanisms involved in tolerance induction, in situ hybridization with radio-labelled synthetic oligonucleotide probes was adopted to enumerate mononuclear cells (MNC) expressing mRNA for the proinflammatory cytokine IFN-gamma, the B cell stimulating IL-4 and the immune response-down-regulating TGF-beta. Popliteal and inguinal lymph nodes from EAMG rats contained elevated numbers of AChR-reactive IFN-gamma, IL-4 and TGF-beta mRNA-expressing cells compared with control rats receiving PBS nasally and injected with FCA only. Nasal tolerance to EAMG was accompanied by decreased numbers of AChR-reactive IFN-gamma and IL-4 mRNA-expressing cells, and strong up-regulation of TGF-beta mRNA-positive cells in lymphoid organs compared with non-tolerized EAMG control rats. The relative affinity of anti-AChR antibodies was lower, but muscle AChR amounts were higher in nasally tolerized rats compared with non-tolerized EAMG control rats. The results suggest that IFN-gamma and IL-4 are central effector molecules in the development of EAMG, and that TGF-beta plays an important role in tolerance induction to EAMG.
Ma
C G
CG
Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Zhang
G X
GX
Xiao
B G
BG
Link
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D000281:Administration, Intranasal; D000818:Animals; D003208:Concanavalin A / Q000276:immunology; D015342:DNA Probes / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000032:analysis / Q000276:immunology; D017403:In Situ Hybridization; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009132:Muscles / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009157:Myasthenia Gravis / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology; D009841:Oligonucleotides / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D011978:Receptors, Nicotinic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014611:Vaccination
D015342:DNA Probes; D007074:Immunoglobulin G; D004676:Myelin Basic Protein; D009841:Oligonucleotides; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D016212:Transforming Growth Factor beta; D003208:Concanavalin A; D015847:Interleukin-4; D007371:Interferon-gamma