title: Interleukin-10 (IL-10) augments allograft arterial disease: paradoxical effects of IL-10 in vivo.
abstract: Interleukin-10 (IL-10) is an anti-inflammatory helper T cell type 2 (Th2) cytokine that modulates Th1-type cytokine production. Graft arterial disease (GAD) is a vascular obliterative process mediated via the Th1 cytokine interferon-gamma (IFN-gamma); allografts in IFN-gamma-deficient animals do not develop GAD. We investigated the effect of IL-10 and anti-IL-10 on GAD in murine heart transplants and whether anti-IL-10 reestablishes GAD in IFN-gamma-deficient hosts. Major histocompatibility complex class II-mismatched hearts were transplanted for 8 weeks into wild-type or IFN-gamma-deficient mice. In one set of experiments, wild-type hosts received daily administration of phosphate-buffered saline (PBS) or increasing IL-10; in a subsequent set of experiments, wild-type hosts received weekly PBS, rat IgG, or anti-IL-10 monoclonal antibody; IFN-gamma-deficient recipients received weekly PBS or anti-IL-10 monoclonal antibody. Explanted allografts were assessed for parenchymal rejection and GAD, cytokine profiles, and adhesion/costimulatory-molecule expression. Exogenous IL-10 resulted in increased Th2-like cytokine production; nevertheless, it exacerbated parenchymal rejection and GAD and increased CD8(+) infiltration. Anti-IL-10 did not significantly affect the extent of rejection or GAD, cytokine profiles, or immunohistology of the allografts in wild-type hosts. Adhesion molecule (CD54 and CD106) expression was not diminished by IL-10 treatment, and costimulatory-molecule (CD80 and CD86) expression was augmented by administration of exogenous IL-10. Allografts in IFN-gamma-deficient recipients showed mild rejection and no GAD, regardless of anti-IL-10 treatment. IL-10 in vivo thus has markedly different effects than predicted from in vitro experience. Although allografts develop Th2-like cytokine profiles treatment with IL-10 causes exacerbated rejection and GAD.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Furukawa
authors.forename: G
authors.initials: G
authors.lastname: Becker
authors.forename: J L
authors.initials: JL
authors.lastname: Stinn
authors.forename: K
authors.initials: K
authors.lastname: Shimizu
authors.forename: P
authors.initials: P
authors.lastname: Libby
authors.forename: R N
authors.initials: RN
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D001162:Arteriosclerosis Obliterans / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D003324:Coronary Artery Disease / Q000209:etiology / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation / Q000009:adverse effects*; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000494:pharmacology / Q000502:physiology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D014184:Transplantation, Homologous
chemical_list: D016753:Interleukin-10