Modulation of experimental autoimmune neuritis in Lewis rats by oral application of myelin antigens.
Experimental autoimmune neuritis (EAN) in Lewis rats is a T cell-mediated disease and serves as an animal model of human inflammatory demyelinating neuropathies. EAN can be induced by immunization with complete bovine peripheral nerve myelin (BPM), the myelin protein P2 or its neuritogenic peptide, each emulsified in complete Freund's adjuvant (CFA). The present study evaluates the effect of oral tolerization with BPM or P2 protein on the development of actively induced EAN. Oral administration of BPM strongly suppressed clinical and histological signs of EAN subsequently induced by BPM/CFA, but feeding of P2 protein alone did not affect its course. In contrast, feeding of BPM did not mitigate the course of EAN subsequently induced by immunization with neuritogenic P2 peptide/CFA. Oral therapy with BPM after onset of myelin-induced EAN only slightly ameliorated the further course of disease, but significantly reduced lethality of this severe form of disease. The findings suggest that immunogenicity of the antigens fed determine strength of tolerance, that downregulation of EAN occurs at the site of immunization and not in the nerve, and that active suppression rather than specific anergization is operative in mediating resistance to EAN. However, only partial tolerance to myelin-induced EAN was achieved in naive animals by transfer of spleen/LN cells from rats orally tolerized with BPM. Although methodic factors may have limited the effect of the cells, the result is suggestive of some contribution of anergy to oral tolerance in the present model. Cholera toxin and LPS were identified as oral adjuvants for BPM and prolonged the state of tolerance. However, LPS exhibited proinflammatory properties if EAN was induced early after BPM/LPS-feeding. Thus, oral application of a mixture of myelin components in combination with cholera toxin may be a useful treatment for chronic inflammatory neuropathies considered autoimmune in nature.
Gaupp
S
S
Department of Neurology, Julius-Maximilians Universität Würzburg, Germany.
Hartung
H P
HP
Toyka
K
K
Jung
S
S
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000627:therapeutic use*; D002417:Cattle; D002772:Cholera Toxin / Q000627:therapeutic use; D004338:Drug Combinations; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects; D008297:Male; D009186:Myelin Sheath / Q000276:immunology*; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D010525:Peripheral Nerves / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew
D000276:Adjuvants, Immunologic; D000941:Antigens; D004338:Drug Combinations; D002772:Cholera Toxin