DOSE-DEPENDENT MECHANISMS RELATE TO NASAL TOLERANCE INDUCTION AND PROTECTION AGAINST EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN LEWIS RATS

Nasal administration of soluble antigens is an exciting means of speci fically down-regulating pathogenic T-cell reactivities in autoimmune d iseases. The mechanisms by which nasal administration of soluble antig ens suppresses autoimmunity are poorly understood. To define further t he principles of nasal tolerance induction, we studied the effects of nasal administration of myelin basic protein (MBP) on experimental aut oimmune encephalomyelitis (EAE) in the Lewis rat. EAE is a CD4(+) T-ce ll-mediated animal model for human multiple sclerosis. Nasal administr ation of guinea-pig (gp)-MBP at a dose as low as 30 mu g/rat can compl etely prevent gp-MBP-induced EAE, whereas nasal administration of bovi ne (b)-MBP is not effective even at a much higher dosage. Cellular imm une responses, as reflected by T-cell proliferation and interferon-gam ma (IFN-gamma)-ELISPOT, were suppressed in rats receiving the two diff erent doses (30 and 600 mu g/rat) of gp-MBP, but not after administrat ion of b-MBP. Rats tolerized with both doses of gp-MBP had also abroga ted MBP-induced IFN-gamma mRNA expression in popliteal and inguinal ly mph node mononuclear cells compared with rats receiving phosphate-buff ered saline nasally. However, adoptive transfer revealed that only spl een mononuclear cells from rats pretreated with a low dose, but not fr om those pretreated with a high dose, of gp-MBP transferred protection to actively induced EAE. Low-dose (30 mu g/rat) gp-MBP-tolerized rats also had high numbers of interleukin-4 (IL-4) mRNA-expressing lymph n ode cells, while high-dose (600 mu g/rat) gp-MBP-tolerized rats had lo w numbers of IL-4 mRNA-expressing lymph node cells. Our data suggest a n exquisite specificity of nasal tolerance. Dose-dependent mechanisms also relate to nasal tolerance induction and protection against EAE in the Lewis rat.