Mucosal tolerance to experimental autoimmune myasthenia gravis is associated with down-regulation of AChR-specific IFN-gamma-expressing Th1-like cells and up-regulation of TGF-beta mRNA in mononuclear cells.
Oral and nasal administration of nicotinic acetylcholine receptor (AChR) to Lewis rats prior to myasthenogenic immunization with AChR and complete Freund's adjuvant (CFA) resulted in prevention or marked decrease of the severity of experimental autoimmune myasthenia gravis (EAMG) and suppression of AChR-specific B-cell responses and of AChR-reactive T-cell function. To examine the involvement of immunoregulatory cytokines and the underlying mechanisms involved in tolerance induction, in situ hybridization with radiolabeled cDNA oligonucleotide proves was adopted to enumerate mononuclear cells (MNC) expressing mRNA for the proinflammatory cytokine interferon-gamma (IFN-gamma), the B cell-stimulating interleukin-4 (IL-4), and the immunosuppressive transforming growth factor-beta (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 to control rats receiving PBS orally or nasally and injected with CFA only. Oral and nasal tolerance 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 when compared to nontolerized 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, Sweden.
Zhang
G X
GX
Xiao
B G
BG
Wang
Z Y
ZY
Link
J
J
Olsson
T
T
Link
H
H
D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D000917:Antibody Formation; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D018482:Muscle, Skeletal / Q000378:metabolism; D009157:Myasthenia Gravis / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000096:biosynthesis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
D000941:Antigens; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007371:Interferon-gamma