ANTIGEN-DRIVEN PERIPHERAL IMMUNE TOLERANCE - SUPPRESSION OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS AND COLLAGEN-INDUCED ARTHRITIS BY AEROSOL ADMINISTRATION OF MYELIN BASIC-PROTEIN OR TYPE-II COLLAGEN

Antigen-driven tolerance is an effective method of suppressing cell-me diated immune responses. We have previously demonstrated that exposure of gut-associated lymphoid tissue to myelin basic protein (MBP) via o ral administration suppresses experimental autoimmune encephalomyeliti s (EAE). To further study presentation of antigen to the immune system by mucosal surfaces as a method of antigen-driven tolerance, the effe ct of inhalation of MBP was investigated. MBP was given as an aerosol to Lewis rats on Days -10, -7, -5, and -3 prior to immunization with M BP in Freund's adjuvant and on Days 0, 2, and 4 following immunization . Aerosolization of MBP completely abrogated clinical EAE in 100% of t reated rats. Central nervous system inflammation and delayed-type hype rsensitivity and antibody responses to MBP were also significantly red uced in aerosol-treated animals. Aerosolization of histone, a basic pr otein of similar weight and charge as MBP, had no effect. Disease was also suppressed with one aerosol treatment on Day -3 or by administeri ng MBP nasally. Aerosolization was more effective than oral administra tion of MBP over a wide dose range (0.005-5 mg). Splenic T cells isola ted from animals postaerosolization adoptively transferred protection to naive animals immunized with MBP. Aerosolization of MBP to animals with relapsing EAE after recovery from the first attack decreased the severity of a subsequent attack. Aerosol and oral MBP were equally eff ective at suppressing the in vitro immune response as measured by prol iferation and interferon-gamma production. We then tested aerosolizati on of a different autoantigen in a different disease model and found t hat aerosolization of type II collagen was effective in suppressing co llagen-induced arthritis. Thus, aerosolization of an autoantigen is a potent method to downregulate an experimental T cell-mediated autoimmu ne disease and suggests that exposure of antigen to lung mucosal surfa ces preferentially generates immunologic tolerance. (C) 1996 Academic Press, Inc.