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Eur J Immunol ; 35(11): 3142-52, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16184515

ABSTRACT

In order to prevent or ameliorate autoimmune disease, it would be desirable to induce central tolerance to peripheral self-antigens. We have investigated whether recombinant antibodies (Ab) that deliver T cell epitopes to antigen-presenting cells (APC) in the thymus can be used to induce thymocyte deletion. Troybodies are recombinant Ab with V regions specific for APC surface molecules that have T cell epitopes genetically introduced in their C domains. When MHC class II-specific Troybodies with the lambda2(315)T cell epitope were injected into lambda2(315)-specific TCR transgenic mice, a profound deletion of (CD4+)8+ thymocytes was observed. MHC class II-specific Troybodies were 10-100-fold more efficient than non-targeting peptide Ab, and 500-fold more efficient than synthetic peptide at inducing deletion. Similar findings were observed when MHC class II-specific Troybodies with the OVA(323-339) T cell epitope were injected into OVA-specific TCR transgenic mice. Although deletion was transient after a single injection, newborn mice repeatedly injected with MHC class II-specific Troybodies for 4 weeks, had reduced antigen-specific T cells in peripheral lymphoid tissues and reduced T cell responses. These experiments suggest that Troybodies constructed to target specifically thymic APC could be useful tools for induction and maintenance of central T cell tolerance in autoimmune diseases.


Subject(s)
Antibodies , Clonal Deletion/immunology , Epitopes, T-Lymphocyte/biosynthesis , Immune Tolerance , Peptides/metabolism , Thymus Gland/metabolism , Animals , Antibodies/genetics , Antibodies/metabolism , Antigen Presentation/genetics , CD4 Antigens/metabolism , CD8 Antigens/metabolism , Histocompatibility Antigens Class II/immunology , Immune Tolerance/genetics , Lymphocyte Count , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, SCID , Mice, Transgenic , Ovalbumin/metabolism , Peptide Fragments/metabolism , Peptides/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Fc/immunology , Recombinant Proteins , T-Lymphocytes/immunology , Thymus Gland/immunology
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