title: Mechanisms of antibody immunotherapy on clonal islet reactive T cells.
abstract: Clinical intervention trials evaluating the efficacy of antibody immunotherapy in type 1 diabetes are in progress. We tested effects on prediabetic islet antigen-specific autoreactive T cells of antithymocyte globulin (ATG) and humanized monoclonal antibodies against CD3 (ChAglyCD3) or CD25 (daclizumab) with regard to downmodulation of the target protein, proliferation, cytokine production, complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), and survival. ATG leads to depletion of autoreactive CD4+ T cells by ADCC, CDC, and apoptosis, whereas anti-CD3 and anti-CD25 inhibited T-cell autoreactivity in a nondepleting fashion. ATG treatment led to a cytokine burst of Th1- and Th2-associated cytokines. Modulation of cytokine release through humanized monoclonal antibodies was moderate and selective: anti-CD25 led to increased release of IL-2 and reduced production of TNFalpha, whereas anti-CD3 decreased release of interferon-y and IL-5 and increased secretion of IL-10. ATG and the humanized monoclonal antibodies displayed contrasting mechanisms of action.
authors.affiliation: Department of Immunohaematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: van de Linde
authors.forename: O M H
authors.initials: OM
authors.lastname: Tysma
authors.forename: J P
authors.initials: JP
authors.lastname: Medema
authors.forename: G
authors.initials: G
authors.lastname: Hale
authors.forename: H
authors.initials: H
authors.lastname: Waldmann
authors.forename: D L
authors.initials: DL
authors.lastname: Roelen
authors.forename: B O
authors.initials: BO
authors.lastname: Roep
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D000077561:Daclizumab; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D005968:Glutamate Decarboxylase / Q000494:pharmacology; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D007527:Isoenzymes / Q000494:pharmacology; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D017252:CD3 Complex; D016207:Cytokines; D007074:Immunoglobulin G; D007527:Isoenzymes; D000077561:Daclizumab; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2