Interleukin (IL)-1 promotes allogeneic T cell intimal infiltration and IL-17 production in a model of human artery rejection.
Interleukin (IL) 1alpha produced by human endothelial cells (ECs), in response to tumor necrosis factor (TNF) or to co-culture with allogeneic T cells in a TNF-dependent manner, can augment the release of cytokines from alloreactive memory T cells in vitro. In a human-mouse chimeric model of artery allograft rejection, ECs lining the transplanted human arteries express IL-1alpha, and blocking IL-1 reduces the extent of human T cell infiltration into the artery intima and selectively inhibits IL-17 production by infiltrating T cells. In human skin grafts implanted on immunodeficient mice, administration of IL-17 is sufficient to induce mild inflammation. In cultured cells, IL-17 acts preferentially on vascular smooth muscle cells rather than ECs to enhance production of proinflammatory mediators, including IL-6, CXCL8, and CCL20. Neutralization of IL-17 does not reduce T cell infiltration into allogeneic human artery grafts, but markedly reduces IL-6, CXCL8, and CCL20 expression and selectively inhibits CCR6(+) T cell accumulation in rejecting arteries. We conclude that graft-derived IL-1 can promote T cell intimal recruitment and IL-17 production during human artery allograft rejection, and suggest that targeting IL-1 in the perioperative transplant period may modulate host alloreactivity.
Rao
Deepak A
DA
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Eid
Raymond E
RE
Qin
Lingfeng
L
Yi
Tai
T
Kirkiles-Smith
Nancy C
NC
Tellides
George
G
Pober
Jordan S
JS
D000818:Animals; D001158:Arteries / Q000033:anatomy & histology / Q000276:immunology / Q000637:transplantation*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D053582:Interleukin-1alpha / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D054399:Receptors, CCR6 / Q000235:genetics / Q000276:immunology; D016038:Skin Transplantation; D014184:Transplantation, Homologous / Q000276:immunology*; D017539:Tunica Intima / Q000166:cytology / Q000276:immunology*
D018925:Chemokines; D016207:Cytokines; D020381:Interleukin-17; D053582:Interleukin-1alpha; D054399:Receptors, CCR6