Nasal tolerance in experimental autoimmune myasthenia gravis (EAMG): induction of protective tolerance in primed animals

Abstract

Nasal administration of microg doses of acetylcholine receptor (AChR) is effective in preventing the development of B cell-mediated EAMG in the Lewis rat, a model for human MG. In order to investigate whether nasal administration of AChR modulates ongoing EAMG, Lewis rats were treated nasally with AChR 2 weeks after immunization with AChR and Freund's complete adjuvant. Ten-fold higher amounts of AChR given nasally (600 microg/rat) were required to ameliorate the manifestations of EAMG compared with the amounts necessary for prevention of EAMG. In lymph node cells from rats receiving 600 microg/rat of AChR, AChR-induced proliferation and interferon-gamma (IFN-gamma) secretion were reduced compared with control EAMG rats receiving PBS only. The anti-AChR antibodies in rats treated nasally with 600 microg/rat of AChR had lower affinity, reduced proportion of IgG2b and reduced capacity to induce AChR degradation. Numbers of AChR-reactive IFN-gamma and tumour necrosis factor-alpha (TNF-alpha) mRNA-expressing lymph node cells from rats treated nasally with 600 microg/rat of AChR were suppressed, while IL-4, IL-10 and transforming growth factor-beta (TGF-beta) mRNA-expressing cells were not affected. Collectively, these data indicate that nasal administration of AChR in ongoing EAMG induced selective suppression of Th1 functions, i.e. IFN-gamma and IgG2b production, but no influence on Th2 cell functions. The impaired Th1 functions may result in the production of less myasthenic anti-AChR antibodies and contribute to the amelioration of EAMG severity in rats treated with AChR 600 microg/rat by the nasal route.

Suppression of ongoing experimental myasthenia by oral treatment with an acetylcholine receptor recombinant fragment

“…This may suggest that IgG2b and IgG2c are involved in the immunopathogenic process taking place in rat EAMG. IgG2b has been previously suggested to be involved in rat EAMG (41), but to our knowledge, there is no former information concerning the role of IgG2c in rat EAMG. Similar shifts in the AChR-specific IgG isotype profile were observed also when oral treatment was given before EAMG induction or when oral treatment was initiated during the chronic phase of EAMG (data not shown).…”

“…These studies have shown that mucosal administration of Torpedo AChR before immunization with AChR prevents the clinical manifestation of the disease and suppresses cellular and humoral responses to the AChR (27)(28)(29). When feeding with Torpedo AChR was performed during the acute phase of EAMG, it led to the elicitation of antibodies to Torpedo and to an increase in autoantibody titers to self muscle AChR (41,42). The priming effect on autoantibody levels induced by feeding with the xenogeneic and highly immunogenic Torpedo AChR and its limited availability hamper its application for therapeutic purposes.…”

Blockade of CD40 Ligand Suppresses Chronic Experimental Myasthenia Gravis by Down-Regulation of Th1 Differentiation and Up-Regulation of CTLA-4

“…Such a shift would be expected to lead to an increase in IgG1, which in the rat is regulated by Th2-type cells. IgG2b and IgG2c, which have been previously suggested to be involved in rat EAMG (2,23), are regulated by Th1 cells.…”

CCL2 recruitment of IL‐6‐producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

“…However, their capacity to produce anti-AChR IgG antibody, in particular IgG2b, was drastically reduced following immunization. Incidentally, IgG2b is highly myasthenogenic [31].…”