title: Activation of human macrophages by allogeneic islets preparations: inhibition by AOP-RANTES and heparinoids.
abstract: During transplantation, pancreatic islets release chemokines which promote macrophage attraction, hampering engraftment of islets. The aim of this study was to modulate chemotaxis and the immune response of human macrophages induced by islets. Human monocyte-derived macrophages of healthy subjects were exposed to supernatants of human islets. Chemotaxis, tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) release were evaluated. To modulate migration, human macrophages were incubated in the presence of aminooxypentane-regulated on activation, normal, T-cell expressed, and secreted (AOP-RANTES), a potent antagonist of CCR5. Chemotactic activity of islets supernatant was modulated by the addition of heparin or heparinoids [pentosan and calix[8S]arene (C8S)]. AOP-RANTES significantly reduced, in a dose-dependent manner, macrophage chemotaxis and cytokine release induced by islets supernatant. The chemotactic index was reduced from 3.05 +/- 0.27 to 0.71 +/- 12, TNF-alpha from 1205 +/- 52 to 202 +/- 12 pg/ml, and IL-1beta from 234 +/- 12 to 10 +/- 6 pg/ml. The trapping of chemokines by heparinoids reduced the chemotactic activity of islets supernatant from 3.05 +/- 0.27 to 1.2 +/- 0.1 with heparin or pentosan and to 1.72 +/- 0.22 with C8S, and also decreased the TNF-alpha release by human macrophages from 1205 +/- 35 to 1000 +/- 26 (C8S), 250 +/- 21 (heparin) and 320 +/- 19 (pentosan) pg/ml, and IL-1beta from 234 +/- 13 to 151 +/- 5 (C8S), 50 +/- 3 (heparin) and 57 +/- 4 (pentosan) pg/ml. In conclusion, AOP-RANTES and heparinoids inhibit human macrophage activation and migration induced by islets supernatant.
authors.affiliation: Centre Européen d'Etude du Diabète, Strasbourg, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Sigrist
authors.forename: José
authors.initials: J
authors.lastname: Oberholzer
authors.forename: Alain
authors.initials: A
authors.lastname: Bohbot
authors.forename: Guy
authors.initials: G
authors.lastname: Esposito
authors.forename: Karim
authors.initials: K
authors.lastname: Mandes
authors.forename: Roger
authors.initials: R
authors.lastname: Lamartine
authors.forename: Christian
authors.initials: C
authors.lastname: Toso
authors.forename: Pascal
authors.initials: P
authors.lastname: Bucher
authors.forename: Michel
authors.initials: M
authors.lastname: Pinget
authors.forename: Laurence
authors.initials: L
authors.lastname: Kessler
mesh_terms: D000328:Adult; D000368:Aged; D065100:CCR5 Receptor Antagonists; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects* / Q000276:immunology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D006496:Heparinoids / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D017077:Culture Media, Conditioned; D006496:Heparinoids; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; C111989:aminooxypentane-RANTES