The Future and Myasthenia

Complement inhibition is an attractive therapeutic approach for MG because it is effective in RODENT EAMG (e.g., ref. 24).

Moreover, anti-C5 inhibitors show short-term safety and are effective in a variety of human disorders, including myocardial infarction [10], coronary artery bypass graft surgery [11], and lung transplantation [12]. Thus, therapeutic approaches based on inhibition of complement activation will likely be tried for MG in the future.

However, the ultimate goal for MG treatment is to eradicate the rogue anti-AChR autoimmune response specifically and reestablish tolerance to the AChR without affecting the other functions of the immune system or causing other adverse effects.

Such targeted immunosuppressive approaches are still far from clinical use. However, their success in EAMG suggests that approaches for specific modulation of the autoimmune anti-AChR response may become part of MG patient care in the next decade. We will summarize here the different approaches that have proven successful for the prevention and treatment of EAMG induced by immunization with AChR. We will also analyze the possible technical and biological limitations to their application for the treatment of human MG.

Approaches that have proven successful in rodent EAMG include the following: (a) administration of AChR or parts of its sequence in a manner known to induce tolerance; (b) depletion of AChR-specific B cells or T cells; and (c) interference with formation of the complex between MHC class II molecules, epitope peptide, T-cell receptor, and CD4 molecule.

Antigen presentation under special circumstances may lead to antigen-specific tolerance in adult animals rather than activated CD4+ T cells. Earlier studies showed that in rats, presentation of AChR epitopes by unsuitable APCs (fixed B cells that had been incubated with AChR under conditions favoring AChR uptake and processing) caused unresponsiveness of the AChR-specific CD4+ T cells to further stimulation with AChR [13]. More recently, several studies have demonstrated that DCs, especially after treatment with TGF-p, IFN-y, or IL-10, when injected into rats with developing or ongoing EAMG, suppressed or ameliorated the myasthenic symptoms [14-16]. The effect was correlated with a reduced production of anti- AChR Abs without a reduced proliferative response of T cells to the AChR. Approaches based on the use of tolerance-inducing APCs, which should present all AChR epitopes and therefore influence all AChR-specific T cells, might be useful for the treatment of MG. Should pulsing of the APCs with human AChR be needed, biosynthetic human AChR subunits could be used as antigens.

Mucosal or subcutaneous administration of AChR or synthetic or biosynthetic AChR peptides to rodents—approaches known to induce antigen-specific tolerance in adult animals—prevented or delayed EAMG development [19]. Depending on the dose of the antigen administered, anergy/deletion of antigen-specific T cells (at high doses) and/or expansion of cells producing immunosuppressive cytokines (TGF-p, IL-4, IL-10) (at low doses) are major mechanisms in mucosal tolerance induction. The use of mucosal toleration procedures in human MG, however, is problematic because those procedures can be a double-edged sword [20]; they reduce AChR-specific CD4+ T-cell responses but may also stimulate AChR-specific B cells to produce Abs, thereby worsening the disease. Also, a large amount of human AChRs would be required, which may be difficult to obtain.

Conjugates of a toxin with AChR or synthetic AChR sequences, when administered to animals with EAMG, eliminated B cells producing anti-AChR Abs [21]. This is probably because the AChR moiety of the conjugate docks onto the membrane- bound Abs of AChR-specific B cells, which can then be killed by the toxic domain. This approach has two caveats. First, the toxin may damage other cells. Second, anti-AChR CD4+ T cells can recruit new B cells to synthesize more anti-AChR Abs.

AChR-specific CD4+ T cells can be specifically eliminated in vitro by APCs genetically engineered to express relevant portions of the AChR, Fas ligand (to eliminate the activated AChR-specific T cells with which they interact), and a portion of Fas-associated death domain, which prevents self-destruction by the Fas ligand [22]. It is not known yet whether this strategy can be safely used to modulate EAMG in vivo.

Activation of CD4+ T cells requires interaction and stable binding of several proteins on the surfaces of the CD4+ T cell and of the APC. In experimental systems, interfering with formation of this complex usually reduced the activity of autoimmune CD4+ T cells. This may be obtained by administering or inducing Abs that recognize the binding site for the antigen of the T-cell receptor (known as T-cell vaccination) [23]. T-cell vaccination is already used in clinical trials for the treatment of multiple sclerosis, rheumatoid arthritis, and psoriasis [24]. It is effective in EAMG, and it is a promising future strategy for the treatment of MG [24]. The mechanisms of action of T-cell vaccination are complex, and they likely include the induction of modulatory CD4+ and CD8+ T cells [24]. Another approach used synthetic peptide analogs of an epitope recognized by autoimmune CD4+ T cells that bind the MHC class II molecules but cannot stimulate the specific CD4+ cells. These are known as altered peptide ligands (APLs). APLs compete with peptide epitopes derived from the autoantigen, thereby turning off the autoimmune response. APLs might also stimulate modulatory anti-inflammatory CD4+ T cells or anergize the pathogenic CD4+ T cells [25]. The rich epitope repertoire of anti-AChR CD4+ T cells in MG patients reduces the therapeutic potential of approaches that interfere with activation of specific CD4+ T cells; targeting only a few epitopes may not significantly reduce the anti-AChR response. Moreover, these treatments are likely to produce only transient improvement that ceases when administration of the anti-T-cell Ab is discontinued.

MG and EAMG have offered unique opportunities to investigate the molecular mechanisms of an Ab-mediated autoimmune disease. Many factors have contributed to making MG the best understood human autoimmune disease. These include the simplicity of the pathogenic mechanism in MG, where NMJ failure explains all symptoms; the deeper understanding of the structure and the function of the NMJ and its molecular components, most notably, the AChR; and the increasing understanding of the mechanisms that modulate immune responses and maintain tolerance. Hopefully increasing knowledge of the immunobiology of MG will form a foundation for designing new and specific therapeutic approaches aimed at curbing the rogue autoimmune response and reestablishing immunological tolerance without interfering with the other immune functions.

If this expectation is fulfilled, MG, which has been a benchmark to understanding autoimmunity in humans, will become a reference point for the design of specific immunosuppressive treatments of other autoimmune Ab-mediated diseases.

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