Inhibition of T-cell responsiveness by nasal peptide administration: influence of the thymus and differential recovery of T-cell-dependent functions - PubMed (original) (raw)

Inhibition of T-cell responsiveness by nasal peptide administration: influence of the thymus and differential recovery of T-cell-dependent functions

B Metzler et al. Immunology. 1999 Jun.

Abstract

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.

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Figures

Figure 1

Figure 1

Establishment and duration of T-cell unresponsiveness in euthymic and adult thymectomized (ATx) mice. Atx mice (b, d, f) or euthymic littermates (a, c, e) received a single 100 μg dose of Ac1–9[4Y] i.n. (•) or PBS (○). Mice were subsequently primed with 50 μg Ac1–9/CFA at one of the indicated time-points after 4Y i.n.; 2 weeks (a, b), 8 weeks (c, d), or 16 weeks (e, f). Ten days later, primed lymphocytes were tested for proliferative responses to Ac1–9 in vitro. Each symbol represents the arithmetic means of triplicate samples, standard deviations were less than 20%. Lymphocyte samples were either derived from individual mice, or pooled from two mice. Each plot shows proliferation data of a representative set of lymphocyte samples with comparable positive (PPD) and negative (medium only) control responses. All samples (three to six independent cell samples per group in two or three experiments per time-point) with comparable negative and positive controls showed similar differences in proliferation.

Figure 2

Figure 2

Partial reversal of protection from EAE 16 weeks after 4Y i.n. Groups of nine mice received a single 100 μg dose of Ac1–9[4Y] i.n. (•) or PBS (○).Sixteen weeks later, EAE was induced with 1 mg SCH/CFA.

Figure 3

Figure 3

Effect of 4Y i.n. on anti-MBP antibody responses. Groups of nine or 10 mice received a single intranasal dose of 100 μg Ac1–9[4Y] (ii, iv, vi, viii; filled bars) or PBS (i, iii, v, vii; open bars). One week (a) or 16 weeks (b) later, all were primed with 1 mg SCH/CFA. After 3 weeks, serum samples from individual mice were assayed by ELISA for anti-MBP antibody concentrations: IgM (i, ii), total IgG (iii, iv), IgG2a (v, vi), and IgG1(vii, vii). Results are expressed in arbitrary units per ml serum as determined from standard curves with positive sera. One unit corresponds to ≈50% maximum absorbance obtained with the standard titration at 1/250 or 1/500 dilution. Sera are numbered in order of increasing concentrations of total IgG. The same numbers apply to all other isotype data plots.

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