Interleukin-17 promotes early allograft inflammation.
Acute cellular rejection of organ transplants is executed by donor-reactive T cells, which are dominated by interferon-gamma-producing cells. As interferon-gamma is dispensable for graft destruction, we evaluated the contribution of interleukin-17A (IL-17) to intragraft inflammation in major histocompatibility complex-mismatched heart transplants. A/J (H-2(a)) cardiac allografts placed into wild-type BALB/c (H-2(d)) mice induced intragraft IL-17 production on day 2 after transplant. Allografts placed into BALB/c IL-17(-/-) recipients demonstrated diminished production of the chemokines CXCL1 and CXCL2 and delayed neutrophil and T cell recruitment. However, by day 7 after transplant, allografts from IL-17(-/-) and wild-type recipients had comparable levels of cellular infiltration. The priming of donor-specific T cells was not affected by the absence of IL-17, and the kinetics of cardiac allograft rejection were similar in wild-type and IL-17(-/-) recipients. In contrast, IL-17(-/-) mice depleted of CD8 T cells rejected A/J allografts in a delayed fashion compared with CD8-depleted wild-type recipients. Although donor-reactive CD4 T cells were efficiently activated in both groups, the infiltration of effector T cells into allografts was impaired in IL-17(-/-) recipients. Our data indicate that locally produced IL-17 amplifies intragraft inflammation early after transplantation and promotes tissue injury by facilitating T cell recruitment into the graft. Targeting the IL-17 signaling network in conjunction with other graft-prolonging therapies may decrease this injury and improve the survival of transplanted organs.
Gorbacheva
Victoria
V
Department of Immunology, The Cleveland Clinic, Cleveland, OH 44195, USA.
Fan
Ran
R
Li
Xiaoxia
X
Valujskikh
Anna
A
D000818:Animals; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D020381:Interleukin-17