Leukocyte-suppressing influences of interleukin (IL)-10 in cardiac allografts: insights from IL-10 knockout mice.
To investigate the role of interleukin (IL)-10 in late graft outcomes, we compared BALB/c donor hearts transplanted into immunosuppressed wild-type or IL-10 gene-deficient (-/-) C57BL recipients (n = 49) at 50 +/- 5 days. There was prominent leukocyte infiltration and parenchymal destruction with more severe vascular occlusion in grafts from IL-10 -/- recipients. An occlusive CD45+ arteritis with medial necrosis occurred with IL-10 deficiency instead of the a-smooth muscle actin-rich arteriosclerosis seen in wild-type recipients. Increased interferon (IFN)-gamma as well as Mac-1, inducible nitric oxide synthase, and allograft inflammatory factor-1 (but not CD3 and IL-4) transcript levels were seen in allografts from IL-10 -/- recipients as assessed by 32p reverse transcription polymerase chain reaction. We then evaluated the contribution of IFN-gamma-mediated responses by neutralizing IFN-gamma. Anti-IFN-gamma monoclonal antibody (MAb) treatment of IL-10 -/- recipients did not improve graft survival, parenchymal rejection, or occlusive arteritis, indicating that these processes are IFN-gamma independent. However, medial smooth muscle cell loss in IL-10 -/- recipients was attenuated by anti-IFN-gamma MAb. Hence, in this transplant model, IL-10 suppresses T cell and macrophage responses in the parenchyma and vasculature and confers a protective effect against late rejection.
Räisänen-Sokolowski
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Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Glysing-Jensen
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Russell
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D000199:Actins / Q000032:analysis; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001161:Arteriosclerosis / Q000276:immunology; D003893:Desmin / Q000032:analysis; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II
D000199:Actins; D000911:Antibodies, Monoclonal; D003893:Desmin; D016177:Macrophage-1 Antigen; D016753:Interleukin-10; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse