Suppression of experimental autoimmune myasthenia gravis by nasal administration of acetylcholine receptor

Ma, Cun‐Gen; Zhang, Guang‐Xian; Xiao, Bao‐Guo; Link, Joanne; Olsson, Tomas; Link, Hans

doi:10.1016/0165-5728(94)00187-s

Cited by 96 publications

(49 citation statements)

References 29 publications

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“…It is of note that levels of AChR-reactive IL-4 mRNAexpressing cells were lower in some lymphoid organs of nasally tolerized rats compared with non-tolerized rats. This agrees with the decreased concentrations of anti-AChR antibodies in serum from tolerized rats (OD shown by our previous study [10]. Here we report that the relative affinity of anti-AChR antibodies is also affected in nasally tolerized rats.…”

Section: Discussionsupporting

confidence: 93%

“…The rats were observed every other day for signs of clinical muscular weakness. Clinical severity of EAMG was scored as follows [10]: 0 no weakness; 1 . 0 mildly decreased activity, weak grip or cry, with fatiguability; 2 .…”

Section: Induction Of Eamg and Clinical Evaluationmentioning

confidence: 99%

“…Upon recognition of AChR and its subunit, AChR-specific IgG-secreting cells and AChR-reactive IFN-mRNA-expressing and IFN--secreting Th1-like cells, as well as AChR-reactive IL-4 mRNA-expressing Th2-like cells are up-regulated in lymphoid organs in EAMG and involved in the pathogenesis of EAMG [6][7][8]. Both oral and nasal administration of Torpedo AChR to Lewis rats before myasthenogenic immunization with AChR resulted in prevention of EAMG and suppression of AChR-specific T and B cell responses [6,7,9,10]. Oral induction of tolerance to EAMG was also related to strong up-regulation of TGFmRNA-expressing cells [8].…”

Section: Introductionmentioning

confidence: 99%

“…Tolerance to EAMG can be induced by nasal administration of AChR [10]. Only 1/1000 of the antigen amount necessary in tolerance induction via the oral route is necessary.…”

Section: Introductionmentioning

confidence: 99%

“…A schedule for the administration of the autoantigen was used [10]. Briefly, rats received into each nostril 30 l of PBS pH 7 .…”

Section: Nasal Tolerance Inductionmentioning

confidence: 99%

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Cellular mRNA expression of interferon-gamma (IFN-γ), IL-4 and transforming growth factor-beta (TGF-β) in rats nasally tolerized against experimental autoimmune myasthenia gravis (EAMG)

et al. 1996

Clinical and Experimental Immunology

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SUMMARYNasal 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 AChRreactive T cell functions. To examine the involvement of immunoregulatory cytokines and the underlying mechanisms involved in tolerance induction, in situ hybridization with radiolabelled synthetic oligonucleotide probes was adopted to enumerate mononuclear cells (MNC) expressing mRNA for the proinflammatory cytokine IFN-°, the B cell stimulating IL-4 and the immune responsedown-regulating TGF-¯. Popliteal and inguinal lymph nodes from EAMG rats contained elevated numbers of AChR-reactive IFN-°, IL-4 and TGF-¯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-°and IL-4 mRNA-expressing cells, and strong up-regulation of TGF-¯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-°a nd IL-4 are central effector molecules in the development of EAMG, and that TGF-¯plays an important role in tolerance induction to EAMG.

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Section: Discussionsupporting

confidence: 93%

Section: Induction Of Eamg and Clinical Evaluationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Tolerance to EAMG can be induced by nasal administration of AChR [10]. Only 1/1000 of the antigen amount necessary in tolerance induction via the oral route is necessary.…”

Section: Introductionmentioning

confidence: 99%

“…A schedule for the administration of the autoantigen was used [10]. Briefly, rats received into each nostril 30 l of PBS pH 7 .…”

Section: Nasal Tolerance Inductionmentioning

confidence: 99%

See 3 more Smart Citations

Cellular mRNA expression of interferon-gamma (IFN-γ), IL-4 and transforming growth factor-beta (TGF-β) in rats nasally tolerized against experimental autoimmune myasthenia gravis (EAMG)

et al. 1996

Clinical and Experimental Immunology

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Oral tolerance: Elucidation of mechanisms and application to treatment of autoimmune diseases

Fowler

Weiner

1997

Biopolymers

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Oral tolerance is the phenomenon of systemic, antigen specific, immunological hyporesponsiveness that results from oral administration of a protein. The mechanism by which tolerance is generated depends on the amount of antigen administered; low doses favor induction of regulatory T cells while higher doses favor clonal deletion and anergy. The regulatory T cells induced by low doses of oral antigen are triggered by the same antigen to secrete cytokines that suppress, in an antigen nonspecific manner, inflammation in the microenvironment where the triggering antigen is located. This makes possible the targeted delivery of antiinflammatory cytokines to a specific tissue without the requirement for identifying the antigen causing the inflammation. This attribute makes active suppression an attractive mechanism for developing therapies for autoimmune diseases. Orally administered autoantigens have been shown to suppress a wide variety of experimental autoimmune diseases and have recently been applied to the treatment of human autoimmune diseases with promising early results. © 1997 John Wiley & Sons, Inc. Biopoly 43: 323–335, 1997

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Cytokines and the pathogenesis of myasthenia gravis

1997

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Myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG) are caused by autoantibodies against nicotinic acetylcholine receptor (AChR) in skeletal muscle. The production of anti‐AChR antibodies is mediated by cytokines produced by CD4+ and CD8+ T helper (Th) cells. Emerging investigations of the roles of cytokines in MG and EAMG have revealed that the Th2 cell related cytokine interleukin 4 (IL‐4), an efficient growth promoter for B‐cell proliferation and differentiation, is important for anti‐AChR antibody production. IL‐6 and IL‐10 have similar effects. The Th1 cytokine IFN‐γ is important in inducing B‐cell maturation and in helping anti‐AChR antibody production and, thereby, for induction of clinical signs and symptoms. Results from studies of time kinetics of cytokines imply that IFN‐γ is more agile at the onset of EAMG, probably being one of the initiating factors in the induction of the disease, and IL‐4 may be mainly responsible for disease progression and persistance. Even though other Th1 cytokines like IL‐2, tumor necrosis factor α (TNF‐α), and TNF‐β as well as the cytolytic compound perforin do not directly play a role in T‐cell‐mediated help for anti‐AChR antibody production, they are actually involved in the development of both EAMG and MG, probably by acting in concert with other cytokines within the cytokine network. In contrast, transforming growth factor β (TGF‐β) exerts immunosuppressive effects which include the down‐regulation of both Th1 and Th2 cytokines in MG as well as EAMG. Suppressive effects are also exerted by interferon α (IFN‐α). Based on elucidation of the role of cytokines in EAMG and MG, treatments that up‐modulate TGF‐β or IFN‐α and/or suppress cytokines that help B‐cell proliferation could be useful to improve the clinical outcome. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 543–551, 1997

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Suppression of experimental autoimmune myasthenia gravis by nasal administration of acetylcholine receptor

Cited by 96 publications

References 29 publications

Cellular mRNA expression of interferon-gamma (IFN-γ), IL-4 and transforming growth factor-beta (TGF-β) in rats nasally tolerized against experimental autoimmune myasthenia gravis (EAMG)

Cellular mRNA expression of interferon-gamma (IFN-γ), IL-4 and transforming growth factor-beta (TGF-β) in rats nasally tolerized against experimental autoimmune myasthenia gravis (EAMG)

Oral tolerance: Elucidation of mechanisms and application to treatment of autoimmune diseases

Cytokines and the pathogenesis of myasthenia gravis

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