Neonatal tolerance to an immunodominant T cell reactivity does not confer resistance to EAMG induction in Lewis rats

Zoda, Thomas E.; Brandon, K. Sack; Krolick, Keith A.

doi:10.1016/0165-5728(94)00159-l

Cited by 4 publications

(2 citation statements)

References 30 publications

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“…This suggests either that the T cell tolerance to the ␣-chain is "leaky" and/or that the T cell response to the other T-AChR chains (␤, ␥, ␦) may be providing help for the B cell response. Studies in mice and rats support the idea that T cell help may be provided to the anti-AChR B cells even when T cells to immunodominant epitopes are tolerized or blocked (55,56). Furthermore, adoptive transfer experiments by Yeh and Krolick (57) suggest that, in the rat MG model, T cells directed against each individual AChR chain can provide help for the anti-AChR B cell response.…”

Section: Discussionmentioning

confidence: 58%

Split Tolerance in a Novel Transgenic Model of Autoimmune Myasthenia Gravis

Stacy¹,

Gelb²,

Koop³

et al. 2002

The Journal of Immunology

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Because it is one of the few autoimmune disorders in which the target autoantigen has been definitively identified, myasthenia gravis (MG) provides a unique opportunity for testing basic concepts of immune tolerance. In most MG patients, Abs against the acetylcholine receptors (AChR) at the neuromuscular junction can be readily identified and have been directly shown to cause muscle weakness. T cells have also been implicated and appear to play a role in regulating the pathogenic B cells. A murine MG model, generated by immunizing mice with heterologous AChR from the electric fish Torpedo californica, has been used extensively. In these animals, Abs cross-react with murine AChR; however, the T cells do not. Thus, to study tolerance to AChR, a transgenic mouse model was generated in which the immunodominant Torpedo AChR (T-AChR) α subunit is expressed in appropriate tissues. Upon immunization, these mice showed greatly reduced T cell responses to T-AChR and the immunodominant α-chain peptide. Limiting dilution assays suggest the likely mechanism of tolerance is deletion or anergy. Despite this tolerance, immunization with intact T-AChR induced anti-AChR Abs, including Abs against the α subunit, and the incidence of MG-like symptoms was similar to that of wild-type animals. Furthermore, evidence suggests that this B cell response to the α-chain receives help from T cells directed against the other AChR polypeptides (β, γ, or δ). This model offers a novel opportunity to elucidate mechanisms of tolerance regulation to muscle AChR and to clarify the role of T cells in MG.

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Section: Discussionmentioning

confidence: 58%

Split Tolerance in a Novel Transgenic Model of Autoimmune Myasthenia Gravis

Stacy¹,

Gelb²,

Koop³

et al. 2002

The Journal of Immunology

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“…A hurdle in designing antigen-specific drug candidates is the polyclonal complexity of autoimmune diseases driven by distinct, diverse autoreactive immune cell repertoires of patients. Indeed, studies on peptide-induced tolerance in EAMG showed that individual AChR peptides failed to produce any therapeutic benefit, despite tolerization against those specific AChR epitopes, highlighting the difficulty in tolerance spreading over bystander epitopes (49,50). The use of a protein autoantigen, presenting a majority of the autoepitopes involved in the autoimmune disease in their native context, allows for patients' individual antigen processing and presentation, thereby potentially reducing requirements associated with peptide-based approaches such as the need for dissection of immunodominant autoepitopes, production of personalized autoepitopes or patient stratification by HLAtype, and reliance on bystander effects to overcome patient heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

A Recombinant Acetylcholine Receptor α1 Subunit Extracellular Domain Is a Promising New Drug Candidate for Treatment Of Myasthenia Gravis

Lazaridis

Fernandez-Santoscoy²,

Baltatzidou

et al. 2022

Front. Immunol.

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Background and AimsMyasthenia gravis (MG) is a T-cell dependent antibody-mediated autoimmune disease in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen, comprising several T and B cell auto-epitopes. We hypothesized that an efficacious drug candidate for antigen-specific therapy in MG should comprise a broad range of these auto-epitopes and be administered in a noninflammatory and tolerogenic context.MethodsWe used a soluble mutated form of the extracellular domain of the α1 chain of the AChR (α1-ECDm), which represents the major portion of auto-epitopes involved in MG, and investigated, in a well-characterized rat model of experimental autoimmune myasthenia gravis (EAMG) whether its intravenous administration could safely and efficiently treat the autoimmune disease.ResultsWe demonstrated that intravenous administration of α1-ECDm abrogates established EAMG, in a dose and time dependent manner, as assessed by clinical symptoms, body weight, and compound muscle action potential (CMAP) decrement. Importantly, the effect was more pronounced compared to drugs representing current standard of care for MG. The protein had a short plasma half-life, most of what could be recovered was sequestered in the liver, kidneys and spleen. Further, we did not observe any signs of toxicity or intolerability in animals treated with α1-ECDm.ConclusionWe conclude that intravenous treatment with α1-ECDm is safe and effective in suppressing EAMG. α1-ECDm is in preclinical development as a promising new drug candidate for MG.

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