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

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.

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Experimental Goodpasture's syndrome in Wistar-Kyoto rats immunized with α3 chain of type IV collagen

Abbate

Kalluri

Corna

et al. 1998

Kidney International

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Experimental Goodpasture's syndrome in Wistar-Kyoto rats immunized with ␣3 chain of type IV collagen.Background. Glomerulonephritis and lung hemorrhage of autoimmune Goodpasture syndrome develop due to immune reactions against epitope(s) of the non-collagenous (NC1) domain of ␣3-chain of type IV collagen [␣3(IV) NC1]. Whether thymic mechanisms have a role in the loss of tolerance to the Goodpasture epitope has not been established. We studied the renal and pulmonary effects of immunization with different forms (monomer, dimer, or hexamer) of ␣3(IV) NC1 collagen in Wistar-Kyoto (WKY) rats, and assessed whether the intrathymic inoculation of the antigen may protect against anti-GBM disease.Methods. WKY rats were immunized with bovine ␣3(IV) monomer, dimer, or hexamer, or with ␣3(IV) NC1 synthetic peptide. Renal function, kidney and lung immunohistology, and circulating and tissue bound antibodies to type IV collagen chains were analyzed. Effects of intrathymic inoculation of antigen on subsequent disease induction were analyzed in WKY rats given ␣3(IV) NC1 dimer or GBM preparation intrathymically 48 hours before immunization.Results. Proteinuria, linear IgG deposition in GBM, and crescentic glomerulonephritis developed in WKY rats immunized with ␣3(IV) NC1 dimer or hexamer. Lesions were dose-dependent upon injections of 10 to 100 g dimer. The ␣3(IV) NC1 monomer induced less severe proteinuria and no crescents. Pulmonary hemorrhage was detectable in 35% of rats immunized with 25 to 100 g ␣3(IV) NC1 dimer; ␣3(IV) synthetic peptide (36 carboxyl terminal) did not induce disease. Rats injected intrathymically with up to 100 g ␣3(IV) NC1 dimer or with GBM 48 hours before immunization were not protected against subsequent development of proteinuria and glomerulonephritis.Conclusions. These findings document that glomerulonephritis and lung hemorrhage can be elicited in WKY rats by immunization with ␣3(IV) NC1. Failure of the intrathymic inoculation of antigen to prevent disease suggests that immunological tolerance cannot be achieved by this intervention, in contrast to other autoimmune conditions, and may imply independent roles for cellular and humoral nephritogenic pathways in anti-GBM nephritis.

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

Cited by 6 publications

References 47 publications

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

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

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

Experimental Goodpasture's syndrome in Wistar-Kyoto rats immunized with α3 chain of type IV collagen

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