title: The reactive D-glucopyranose moiety of streptozotocin is responsible for activation of macrophages and subsequent stimulation of CD8+ T cells.
abstract: The antitumor drug streptozotocin (STZ) is commonly used as a diabetogenic compound in animal models. At relatively low doses, STZ-induced beta cell destruction is associated with Th1-driven type 1 immune reactions, including macrophages (MPhi) and IFN-gamma-producing CD8(+) T cells. STZ induces similar Th1-dependent effects in the popliteal lymph node assay (PLNA), and because this assay allows straightforward examination of early immunostimulating processes, the PLNA was used to further examine the importance of MPhi and structural properties of STZ in relation to the induction of type 1 immune responses. Results show that elimination of MPhi with clodronate-containing liposomes prior to exposure to STZ prevents the occurrence of some (CD8(+) T cell activation, IFN-gamma production, and tissue destruction) but not all (IgG2a formation) type 1 immune responses. It appeared that stimulation of MPhi depends on the d-glucopyranose moiety of STZ, as well as on the intact reactive N-methyl-N-nitrosourea (MNU) moiety. However, the MNU moiety suffices to induce IgG2a formation. In addition, STZ-derived nitric oxide may have modulating effects on the elicitation of STZ-induced immune responses. Present results support the idea that MPhi activation is indispensable for the STZ-induced tissue destructive type 1 responses and that various STZ-induced type 1 immune responses are differently regulated.
authors.affiliation: Institute for Risk Assessment Sciences, Immunotoxicology, Utrecht University, P.O. Box 80176, NL 3508 TD Utrecht, The Netherlands. s.nierkens@iras.uu.nl
authors.forename: Stefan
authors.initials: S
authors.lastname: Nierkens
authors.forename: Rob
authors.initials: R
authors.lastname: Bleumink
authors.forename: Marianne
authors.initials: M
authors.lastname: Bol
authors.forename: Ine
authors.initials: I
authors.lastname: Hassing
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Raymond
authors.initials: R
authors.lastname: Pieters
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000737:chemistry*; D007074:Immunoglobulin G / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D008770:Methylnitrosourea / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D013311:Streptozocin / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D007074:Immunoglobulin G; D008081:Liposomes; D004002:Clodronic Acid; D009569:Nitric Oxide; D013311:Streptozocin; D008770:Methylnitrosourea; D007371:Interferon-gamma; D005947:Glucose