Selective elimination of antigen-specific line T cells and ex vivo antigen-primed lymph node cells by antigen-targeted drug-labeled antigen-presenting cell membranes.
Since antigen-specific autoaggressive T cells have been found in association with many autoimmune diseases, a treatment to eliminate such antigen-specific T cell clones was developed. The complex of peptide antigen and class II MHC protein is used to target a cytotoxic drug to antigen-specific T cells. The drug is bound covalently to antigen-presenting cells (APC) and protein antigens (Ag) are added to the cells for processing and presentation of peptides. The APC contain class II MHC (Ia) protein to present the peptide Ag to the T cell receptor and adhesion proteins for optimal interaction with the T cell. Either the Ag-bearing intact APC or Ia+ membranes shed or released spontaneously from them were used as drug carriers to target the drug to the T cells. The drugs being used are phototoxic compounds. When irradiated with light of an appropriate wavelength, they give off toxic free radicals and singlet oxygen. These toxic by-products are short-lived and damage cells only in their immediate vicinity, cutting down on nonspecific side effects. APC from thymus cells, or their shed membranes bearing Ia-Ag peptide complexes, were able to target the phototoxic drug specifically to Ag-specific T line cells and ex vivo Ag-specific lymph node cells. Proliferation of the target T cells was inhibited at a three to four times lower drug concentration than required to affect control T cells. The Ag-specific effect was inhibited by anti-Ia antibody and by drug-free membranes carrying the Ag-Ia complex. This indicated that the antigen-specific phototoxic effect was mediated by interaction of the Ag-Ia complex with the T cell receptor.
Chang
N H
NH
Department of Biochemistry, University of Toronto, Canada.
Boggs
J M
JM
D000276:Adjuvants, Immunologic / Q000737:chemistry; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D017637:Clonal Deletion / Q000276:immunology*; D000939:Epitopes; D006433:Hemocyanins / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007114:Immunization; D008198:Lymph Nodes / Q000166:cytology* / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D011721:Pyrenes; D051381:Rats; D011917:Rats, Inbred Lew; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013194:Staining and Labeling; D013601:T-Lymphocytes / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D011721:Pyrenes; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin; D006433:Hemocyanins; C030984:pyrene; C032808:keyhole-limpet hemocyanin