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Tolerization of an established αb-crystallin-reactive T-cell response by intravenous antigen

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Author: Verbeek, R. · Mark, K. van der · Wawrousek, E.F. · Plomp, A.C. · Noort, J.M. van
Type:article
Date:2007
Institution: TNO Kwaliteit van Leven
Source:Immunology, 3, 121, 416-426
Identifier: 240065
doi: doi:10.1111/j.1365-2567.2007.02592.x
Keywords: Biology · Biomedical Research · αB-crystallin · Autoimmunity · Multiple sclerosis · T cells · Tolerance · alpha crystallin · alphab crystallin · antibody · autoantigen · Freund adjuvant · ovalbumin · epitope · gamma interferon · immunoglobulin G · recombinant protein · animal cell · animal experiment · antibody blood level · antibody response · antigen specificity · article · cellular immunity · controlled study · delayed hypersensitivity · dose response · drug dose comparison · drug efficacy · immune response · immunization · immunological tolerance · immunoregulation · mouse · multiple sclerosis · nonhuman · priority journal · protein deficiency · T lymphocyte activation · animal · biosynthesis · cell culture · dendritic cell · immunology · intravenous drug administration · lymphocyte activation · T lymphocyte subpopulation · time · alpha-Crystallin B Chain · Animals · Autoantigens · Cells, Cultured · Dendritic Cells · Dose-Response Relationship, Immunologic · Epitopes · Hypersensitivity, Delayed · Immune Tolerance · Immunoglobulin G · Injections, Intravenous · Interferon Type II · Lymphocyte Activation · Mice · Multiple Sclerosis · Recombinant Proteins · T-Lymphocyte Subsets · Time Factors

Abstract

Tolerance induction to prevent activation of a naïve T-cell repertoire has been well documented in rodents and can be readily achieved by intravenous, oral or intranasal administration of antigen in the absence of adjuvants. In autoimmune diseases such as multiple sclerosis (MS) the presence of an established memory/effector T-cell repertoire against self-antigens is likely to be more relevant than the potential reactivity of naive T cells. Methods to eliminate such an established T-cell response are less well understood. In this study, we explored the effectiveness of intravenous soluble antigen to eliminate a pre-existing T-cell response against αB-crystallin, a candidate autoantigen in MS. We used mice that are deficient for the target antigen. This condition allowed for a vigourous T-cell and antibody response to develop upon immunization, and eliminated all possible endogenous mechanisms of tolerance for αB-crystallin that are found in normal rodents. When applied 3 weeks after priming with αB-crystallin, intravenous administration of soluble antigen almost completely abrogated the established T-cell response in a dose-dependent manner as evidenced by T-cell non-responsiveness in tolerized animals to a re-challenge with antigen in complete Freund's adjuvant. Evaluating delayed-type hypersensitivity responses after tolerance induction revealed that the tolerizing effect was achieved within 24 hr. Furthermore, the tolerizing effect was found to be antigen-specific and long lasting. In contrast, serum antibody levels were markedly increased. Our data clarify that in the absence of any natural form of immune regulation, antigen-specific memory/effector T cells can be effectively silenced by intravenous antigen. © 2007 Blackwell Publishing Ltd.