Oral administration of acetylcholine receptor: Effects on experimental myasthenia gravis

Abstract

The abnormality in myasthenia gravis (MG) is a deficiency of acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune attack. Although immunosuppressive drugs are usually beneficial in MG, they produce generalized suppression of the immune system. Treatment should specifically inhibit the immune response to AChR. Oral administration of an antigen may induce specific tolerance and has recently been tested for treatment of several cell-mediated experimental and human autoimmune diseases. In this study, we investigated the effects of oral administration of AChR in an experimental rat model of MG (EAMG), which is antibody mediated. Lewis rats were fed various doses of purified or unpurified Torpedo AChR, or a control antigen, ovalbumin (OVA). They were then immunized with AChR or OVA. We measured antibody responses to Torpedo AChR or OVA, autoantibody responses to rat AChR, cellular responses, cellular suppressive effects, and clinical status. Our results showed that AChR feeding prevented clinical signs of EAMG. It initially primed, then inhibited, antibody responses to foreign (Torpedo) AChR and self (rat) AChR, with a delayed onset. Cellular responses to AChR, measured by lymphocyte proliferation and interleukin-2 production, were markedly inhibited. The effects were dose dependent. Unpurified AChR given in comparable amounts was far less effective than pure AChR. OVA feeding had similar, but even more potent effects on humoral and cellular immune responses to OVA, but did not inhibit clinical EAMG or AChR responses. Moderate nonspecific suppression by splenic T cells from orally treated animals was demonstrated in vitro. We conclude that oral therapy is beneficial in EAMG and may prove effective in MG patients. Early priming and delayed inhibition suggest that a molecule with less immunogenic potential than intact AChR might be more effective as a therapeutic agent.

'Split tolerance’ induction by intrathymic injection of acetylcholine receptor in a rat model of autoimmune myasthenia gravis; implications for the design of specific immunotherapies

“…In this regard, a gradient of sensitivity to tolerance induction with Thi > Th2 > B cells has been described recently [26]. Feeding Torpedo AChR induced tolerance in EAMG, in which the clinically relevant autoantibody (anti-rat AChR) was more inhibited than antiTorpedo AChR antibody [35]. In the present study, even the autoantibody was not suppressed in the thymically tolerized rats.…”

“…Our test on the elTect of intrathymic injection of AChR 7 days before active immunization resulted in a failure of inhibition of antibody production. Such results may be in part due lo the striking immunogenicity or insolubility of AChR [33][34][35]. Alternatively, the dosage of AChR may have been too small to induct!…”

Suppression of myasthenogenic responses of a T cell line by a dual altered peptide ligand by induction of CD4+CD25+regulatory cells

“…T helper 1 cytokines IFN-␥ and IL-2 have been shown to be involved in the pathogenesis of experimental autoimmune MG (28,29). To test the effect of the dual APL on the p195-212-specific T cells, cells of the line were incubated with p195-212 with or without the dual or reversed dual APL for 24 (IFN-␥, IL-2, and IL-10) or 48 (TGF-␤) h. As shown in Fig.…”

Therapeutic vaccines in autoimmunity

“…One of the most significant effects of the dual APL on the cytokine balance was the up-regulation of TGF-␤. It was demonstrated that secretion of TGF-␤ was up-regulated (in parallel to down-regulation of IFN-␥ secretion) in mice and rats after oral or nasal administration of AChR, and that correlated with an improvement in their clinical status (55)(56)(57)(58). Furthermore, a correlation was found between clinical remission and increase in TGF-␤ expression in mononuclear cells of MG patients (59).…”