Regulation of house dust mite responses by intranasally administered peptide: transient activation of CD4+ T cells precedes the development of tolerance in vivo.
We have previously demonstrated that intranasal (i.n.) administration of an immunodominant peptide (p1-111-139) derived from the house dust mite (HDM) allergen Der p 1 inhibits antigen-specific CD4+ T cell responses in H-2b mice. Here we report that i.n. peptide induced a rapid but transient activation of MHC class II restricted CD4+ T cells that peaked 4 days after peptide treatment and was of similar magnitude to that induced by parenteral immunization with antigen in adjuvant. During the early phase of the response lymph node and splenic T cells secreted a range of lymphokines when re-stimulated in vitro with p1 111-139; however, by day 14 IL-2 and IFN-gamma secretion by T cells were down-regulated. Mice deficient in CD8+ T cells became tolerant by i.n. treatment with peptide, suggesting that CD8+ T cells are not involved in down-regulating the CD4+ T cell response. Rechallenging mice with a single dose of p1 111-139 21 days after the initial treatment elicited a further transient T cell response, which was subsequently down-regulated over time. Although the i.n. peptide induced a strong transient CD4+ T cell response, only low levels of peptide-specific antibodies were detected either after the initial or subsequent i.n. exposures to p1 111-139. Our findings address the mechanisms underlying peripheral T cell tolerance following i.n. administration of a high dose of immunogenic peptide and have implications for understanding the consequences of peptide immunothearapy.
Hoyne
G F
GF
Department of Biology, Imperial College of Science, Technology and Medicine, London, UK.
Askonas
B A
BA
Hetzel
C
C
Thomas
W R
WR
Lamb
J R
JR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D039741:Antigens, Dermatophagoides; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000187:drug effects; D007108:Immune Tolerance; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007377:Interleukin-3 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL
D000911:Antibodies, Monoclonal; D039741:Antigens, Dermatophagoides; D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007376:Interleukin-2; D007377:Interleukin-3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor