Immune tolerance induced by polyethylene glycol-conjugate of protein antigen: clonal deletion of antigen-specific Th-cells in the thymus.
Polyethylene glycol (PEG) conjugates of protein antigens induce antigen-specific immune tolerance of helper T (Th)-cells. However, the mechanism of this Th-cell tolerance has remained unelucidated. Using transgenic mice with ovalbumin (OVA)-specific T-cell receptor (TCR) genes, we examined the response of OVA-specific Th-cells towards tolerogenic PEG-conjugate of OVA in vitro and in vivo. When stimulated with PEG--OVA in vitro, transgenic OVA-specific Th-cells proliferated and produced interleukin 2, the levels of which were comparable to those induced by unmodified OVA. In contrast, PEG--OVA administered into the circulation of transgenic mice induced unresponsiveness in peripheral OVA-specific Th-cells. Moreover, in the thymus of these transgenic mice, the frequency of immature CD4+CD8+ (double positive) thymocytes was reduced. A similar phenomenon was not observed in transgenic mice treated with unmodified OVA. As autoreactive T-cells are known to be clonally deleted at the immature double positive stage in the thymus. Th-cell tolerance induced by PEG--protein antigens is at least in part mediated by central tolerance in the thymus, and is likely caused by the markedly enhanced stability of PEG--protein conjugates in the circulatory system.
Saito
T
T
Department of Biomedical Engineering, Toin University of Yokohama, Japan.
Kumagai
Y
Y
Hiramatsu
T
T
Kurosawa
M
M
Sato
T
T
Habu
S
S
Mitsui
K
K
Kodera
Y
Y
Hiroto
M
M
Matsushima
A
A
Inada
Y
Y
Nishimura
H
H
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002455:Cell Division; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000187:drug effects* / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors
D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011092:Polyethylene Glycols; D010047:Ovalbumin