Induction of central T cell tolerance: recombinant antibodies deliver peptides for deletion of antigen-specific (CD4+)8+ thymocytes.
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.
Schjetne
Karoline Western
KW
Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, Oslo, Norway. k.w.schjetne@medisin.uio.no
Thommesen
John Einar
JE
Fredriksen
Agnete Brunsvik
AB
Lunde
Elin
E
Sandlie
Inger
I
Bogen
Bjarne
B
D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000378:metabolism; D017951:Antigen Presentation / Q000235:genetics; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D017637:Clonal Deletion / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D011961:Receptors, Fc / Q000276:immunology; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D015704:CD4 Antigens; D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; C111390:OVA 323-339; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D011961:Receptors, Fc; D011994:Recombinant Proteins; D010047:Ovalbumin