Mechanisms of nasal tolerance induction in experimental autoimmune myasthenia gravis: identification of regulatory cells.
Autoantigen administration via nasal mucosal tissue can induce systemic tolerance more effectively than oral administration in a number of experimental autoimmune diseases, including Ab-mediated experimental autoimmune myasthenia gravis, a murine model of myasthenia gravis. The mechanisms underlying nasal tolerance induction are not clear. In this study, we show that nasal administration of acetylcholine receptor (AChR) in C57BL/6 mice, before immunizations with AChR in adjuvant, results in delayed onset and reduced muscle weakness compared with control mice. The delayed onset and reduced muscle weakness were associated with decreased AChR-specific lymphocyte proliferation and decreased levels of anti-AChR Abs of the IgG2a and IgG2b isotypes in serum. The clinical and immunological changes in the AChR-pretreated C57BL/6 wild-type (wt) mice were comparable with those observed in AChR-pretreated CD8-/- mice, indicating that CD8+ T cells were not required for the generation of nasal tolerance. AChR-pretreated wt and CD8-/- mice showed augmented TGF-beta and reduced IFN-gamma responses, whereas levels of IL-4 were unaltered. Splenocytes from AChR-pretreated wt and CD8-/- mice, but not from CD4-/- mice, suppressed AChR-specific lymphocyte proliferation. This suppression could be blocked by Abs against TGF-beta. Thus, our results demonstrate that the suppression induced in the present model is independent of CD8+ T cells and suggest the involvement of Ag-specific CD4+ Th3 cells producing TGF-beta.
Shi
F D
FD
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
Li
H
H
Wang
H
H
Bai
X
X
van der Meide
P H
PH
Link
H
H
Ljunggren
H G
HG
D000818:Animals; D000906:Antibodies / Q000097:blood; D001324:Autoantigens / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics; D016827:CD8 Antigens / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018908:Muscle Weakness / Q000276:immunology / Q000517:prevention & control; D009157:Myasthenia Gravis / Q000276:immunology* / Q000517:prevention & control; D009297:Nasal Mucosa / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology
D000906:Antibodies; D001324:Autoantigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D007376:Interleukin-2; D011950:Receptors, Cholinergic; D007371:Interferon-gamma