title: Upregulation of interleukin-10 and inhibition of alloantigen responses by transferrin and transferrin-derived glycans.
abstract: Previous studies have shown that critically timed administration of transferrin (Tf) facilitates induction of immunologic unresponsiveness. Here, we determined in mixed leukocyte culture (MLC) and in concanavalin A (ConA)-driven cultures the effect of exogenous Tf and Tf-derived glycans (Tf-Gly) on lymphocyte proliferation. In cultures of human blood lymphocytes, Tf inhibited selectively alloantigen-driven proliferation in MLC, but not ConA-stimulated lymphocyte proliferation. Deglycosylation of Tf abrogated the inhibitory effect of Tf on alloantigen-induced lymphocyte proliferation, and, consistent with a role for glycans, an effect qualitatively and quantitatively similar to Tf was exerted by purified Tf-Gly. Glycans isolated from other proteins, for example, immunoglobulin G (IgG) or fibrinogen, failed to inhibit alloantigen-induced proliferation selectively. Rather, they suppressed lymphocyte proliferation in a non-specific manner. Determination of cytokines in MLC supernatant showed a downregulation of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-2, and IL-12 (p40), along with an upregulation of IL-10, a pattern entirely consistent with the observed effects of Tf and Tf-Gly on alloantigen-induced lymphocyte proliferation. The effect of Tf on MLC was directly IL-10-dependent. IL-10 levels were inversely correlated with lymphocyte proliferation and CD86 expression. Neutralization of IL-10 by anti-IL-10 monoclonal antibody (mAb) blocked the effect of Tf. The MLC-modulating effect of Tf (or Tf-Gly) was not dependent upon the Tf receptor CD71 but appeared to be mediated by a Gly-responsive receptor. These data suggest a role of Tf, and, in particular, Tf-Gly, in allo-interactions that is independent from the role of Tf in iron metabolism, and appears to involve co-stimulatory signals.
authors.affiliation: Fred Hutchinson Cancer Research Center and University of Washington, Seattle 98109-1024, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lesnikova
authors.forename: V
authors.initials: V
authors.lastname: Lesnikov
authors.forename: S
authors.initials: S
authors.lastname: Arrighi
authors.forename: G
authors.initials: G
authors.lastname: Kistler
authors.forename: W
authors.initials: W
authors.lastname: Pierpaoli
authors.forename: H J
authors.initials: HJ
authors.lastname: Deeg
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000494:pharmacology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000494:pharmacology; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007519:Isoantigens / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D011134:Polysaccharides / Q000494:pharmacology*; D011990:Receptors, Transferrin; D014168:Transferrin / Q000031:analogs & derivatives / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C068126:CD71 antigen; D016207:Cytokines; D007074:Immunoglobulin G; D007519:Isoantigens; D011134:Polysaccharides; D011990:Receptors, Transferrin; D014168:Transferrin; D003208:Concanavalin A; D016753:Interleukin-10