Inhibition of T-cell responsiveness by nasal peptide administration: influence of the thymus and differential recovery of T-cell-dependent functions.
We have previously demonstrated that intranasal (i.n.) administration of the major encephalitogenic peptide, Ac1-9 of myelin basic protein (MBP), inhibited T-cell responsiveness in vitro and induced tolerance in the H-2u mouse model of experimental autoimmune encephalomyelitis (EAE). The peptide analogue Ac1-9[4Y] with high-affinity binding to the I-Au major histocompatibility complex (MHC) class II molecule was the most effective tolerogen. Here, we show that mice pretreated with 4Y i.n. and primed with myelin had strongly reduced levels of anti-MBP immunoglobulin G2a (IgG2a) and IgG1, demonstrating that both T helper 1 (Th1) and Th2 functions were inhibited in vivo. Since peptide administered i.n. was shown to be functionally relevant in the thymus, the time interval between 4Y i.n. and subsequent priming was varied in euthymic and adult thymectomized (ATx) mice, to examine the duration of in vitro cell unresponsiveness in the presence or absence of a thymus. For intervals of 1-6 weeks, inhibition of T-cell proliferation was virtually complete in both euthymic and ATx mice. From 8 weeks onwards, responsiveness slowly recovered in euthymic but not in ATx mice. With an interval of 16 weeks, substantial recovery of T-cell responsiveness in vitro in euthymic mice was reflected by a low degree of protection from EAE in vivo. By contrast, anti-MBP IgG2a and IgG1 antibody responses were still significantly reduced. These findings suggest that T-cell unresponsiveness by peptide i.n. represents a thymus-independent, peripheral phenomenon, the reversal of which is confined to new T cells being exported from the thymus. As observed for EAE and antibody responses, the kinetics of recovery may vary for different effector functions.
Metzler
B
B
Department of Pathology and Microbiology, University of Bristol School of Medical Sciences, University Walk, Bristol, UK.
Wraith
D C
DC
D000281:Administration, Intranasal; D000818:Animals; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
D007074:Immunoglobulin G; D007075:Immunoglobulin M; D004676:Myelin Basic Protein; D010455:Peptides