NASAL ADMINISTRATION OF MYELIN BASIC-PROTEIN PREVENTS RELAPSING EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN DA RATS BY ACTIVATING REGULATORY CELLS EXPRESSING IL-4 AND TGF-BETA MESSENGER-RNA

This study explores nasal administration of myelin basic protein (MBP) as a potential means of inducing tolerance to relapsing experimental autoimmune encephalomyelitis (PR-EAE), an experimental multiple sclero sis (MS) model that was induced in DA rats by immunization with rat sp inal cord homogenate and incomplete Freund's adjuvant. DA rats receive d a total dosage of 0, 6, 60, 600 mu g/rat of bovine MBP on ten consec utive days prior to immunization. EAE with typical course was observed in control rats receiving only PBS nasally, and in rats receiving 6 m u g/rat of MBP. Rats receiving 60 mu g/rat of MBP developed acute EAE but no relapse during 60 days of observation post immunization (p.i.). Only one of eight rats receiving 600 mu g/rat of IL SBP developed sli ght, transient EAE. This protection was confirmed at the histology lev el and was associated with decreased levels of MBP-reactive IFN-gamma secreting Th1-like spleen cells on day 13 and 60 p.i. Rats receiving 6 0 and 600 mu g/rat of MBP showed decreased serum anti-MBP IgG2b antibo dy levels on day 60 p.i., and rats receiving 600 mu g/rat of MBP had m arginally increased anti-MBP IgG1 antibody levels in serum compared to control EAE rats. Cytokine mRNA profiles in central nervous system (C NS) and spleen mononuclear cells were evaluated. Dose-dependent reduct ion of TNF-alpha mRNA expression were observed both in CNS and in sple nocytes. Increased IL-4 and TGF-beta mRNA expression were observed in CNS of low (6 mu g/rat) and median (60 mu g/rat) dose of MBP tolerized rats and in splenotytes of rats tolerized with 600 mu g/rat of MBP. W e conclude that nasal administration of MBP in DA rat prevents EAE ind uced by immunization with whole rat spinal cord homogenate that, besid es MBP, contains multiple antigenic myelin proteins. A mechanism invol ving MBP-reactive regulatory cells expressing IL-4 and TGF beta mRNA a cts as part in the induction of this tolerance. (C) 1997 Elsevier Scie nce B.V.