Nasal administration of multiple antigens suppresses experimental autoimmune myasthenia gravis, encephalomyelitis and neuritis

Shi, Fu‐Dong; Bai, Xue‐Feng; Xiao, Bao‐Guo; Meide, P. H. Van Der; Link, Hans

doi:10.1016/s0022-510x(97)00232-3

Cited by 29 publications

(12 citation statements)

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“…This explains why adjuvants such as mycobacteria have to be included when EAE is induced. In fact, immunization with myelin autoantigens without adjuvants leads to tolerance to the autoantigen [26,27]. MyD88 is an adaptor molecule for multiple receptors, which complicates the understanding of TLR role in EAE.…”

Section: Discussionmentioning

confidence: 99%

Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis

et al. 2008

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Innate immune mechanisms essential for priming encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. Experimental autoimmune encephalomyelitis (EAE) is a IL-17-producing Th (Th17) cell-mediated autoimmune disease and an animal model of multiple sclerosis. To investigate how upstream TLR signals influence autoimmune T cell responses, we studied the role of individual TLR and MyD88, the common TLR adaptor molecule, in the initiation of innate and adaptive immune responses in EAE. Wild type (WT) C57BL/6, TLR-deficient and MyD88-deficient mice were immunized with myelin oligodendrocyte glycoprotein (MOG) in CFA. MyD88 -/-mice were completely EAE resistant. Purified splenic myeloid DC (mDC) from MyD88 -/-mice expressed much less IL-6 and IL-23, and serum and T cell IL-17 were absent. TLR4-/-and TLR9 -/-mice surprisingly exhibited more severe EAE symptoms than WT mice. IL-6 and IL-23 expression by mDC and Th17 responses were higher in TLR4 -/-mice, suggesting a regulatory role of TLR4 in priming Th17 cells. IL-6 expression by splenocytes was higher in TLR9 -/-mice. Our data suggest that MyD88 mediates the induction of mDC IL-6 and IL-23 responses after MOG immunization, which in turn drives IL-17-producing encephalitogenic Th17 cell activation. Importantly, we demonstrate that TLR4 and TLR9 regulate disease severity in MOGinduced EAE.

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Section: Discussionmentioning

confidence: 99%

Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis

et al. 2008

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“…The idea of tolerizing the immune system to the AChR by administering AChR peptides orally or nasally has been investigated in experimental MG models [146,147], but has been difficult to translate in the clinic. DNA vaccinations have also been proposed, but, as with peptide vaccines, a primary concern is the potential for exacerbation of the anti-AChR immune response.…”

Section: Vaccination Approachesmentioning

confidence: 99%

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

2016

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Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle-specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets.

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“…The particular mucosal site to which antigen is targeted may also determine the nature of the immune response. It has been suggested that tolerance induction is more effective when antigen is delivered intranasally (3,4) or as inhaled aerosol (5) rather than by the oral route. In the nonobese diabetic (NOD) mouse, intranasal insulin B-chain peptide 9 -23 (6), GAD peptides (7), or inhaled insulin aerosol (8) induce tolerance, which, as with repeated low-dose oral insulin (9 -11), is transferable by regulatory T-cells into nontolerized recipients.…”

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confidence: 99%

Mucosal Antigen Primes Diabetogenic Cytotoxic T-Lymphocytes Regardless of Dose or Delivery Route

et al. 2001

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Administration of antigens via mucosal routes, such as orally or intranasally, can induce specific immunological tolerance and has been used as a rational basis for the treatment of autoimmune diseases, including type 1 diabetes. Recently, however, orally delivered antigens were shown to induce CD8 cytotoxic T-lymphocytes (CTLs) capable of causing autoimmune diabetes. In this report, we have examined several mucosal routes for their ability to induce CTLs and autoimmune diabetes, with the aim of identifying approaches that would maximize tolerance and minimize CTL generation. In normal C57BL/6 mice, ovalbumin (OVA) delivered by either the oral or nasal routes or by aerosol inhalation was able to prime CTL immunity in both high-and low-dose regimens. To address the relevance of these CTLs to autoimmune disease, OVA was given to mice that transgenically expressed this antigen in their pancreatic ␤-cells. Irrespective of antigen dose or the route of delivery, mucosal OVA triggered diabetes, particularly after intranasal administration. These findings suggest that CTL immunity is likely to be a consequence of mucosal antigen delivery, regardless of the regimen, and should be considered in the clinical application of mucosal tolerance to autoimmune disease prevention.

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Nasal administration of multiple antigens suppresses experimental autoimmune myasthenia gravis, encephalomyelitis and neuritis

Cited by 29 publications

References 50 publications

Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis

Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

Mucosal Antigen Primes Diabetogenic Cytotoxic T-Lymphocytes Regardless of Dose or Delivery Route

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