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* Transplant Research Center "Chiara Cucchi De Alessandri & Gilberto Crespi," Mario Negri Institute for Pharmacological Research, Bergamo, Italy;
Department of Immunology and Organ Transplantation, Ospedali Riuniti-Mario Negri Institute for Pharmacological Research, Bergamo, Italy;
Istituto Clinico Humanitas, IRCCS, Rozzano, Italy; and
Department of Translational Medicine, University of Milan, Milan, Italy
Members of the TLR/IL-1R superfamily mediate ischemia/reperfusion injury and initiate immune response in transplanted organs. In this study, we tested the hypothesis that Toll-IL-1R8 (TIR8), a negative regulator of TLR/IL-1R highly expressed in the kidney, modulates immune cell activation underlying kidney rejection. In a mouse model of fully mismatched kidney allotransplantation in which the graft is spontaneously accepted, intragraft Tir8 expression was enhanced compared with naive kidneys. Targeted deletion of Tir8 in the graft exerted a powerful antitolerogenic action leading to acute rejection. Similarly, in a mouse model of kidney graft acceptance induced by costimulation blockade, most Tir8–/– grafts were acutely rejected. Despite similar levels of TLR4, IL-1R, and their ligands, the posttransplant ischemia/reperfusion-induced inflammatory response was more severe in Tir8–/– than in Tir8+/+ grafts and was followed by expansion and maturation of resident dendritic cell precursors. In vitro, Tir8–/– dendritic cell precursors acquired higher allostimulatory activity and released more IL-6 upon stimulation with a TLR4 ligand and TNF-
than Tir8+/+ cells, which may explain the increased frequency of antidonor-reactive T cells and the block of regulatory T cell formation in recipients of a Tir8–/– kidney. Thus, TIR8 acts locally as a key regulator of allogeneic immune response in the kidney. Tir8 expression and/or signaling in donor tissue are envisaged as a novel target for control of innate immunity and amelioration of graft survival.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was partially supported by grants from Foundation ART for Research on Transplantation (Milan, Italy), Ministero della Salute, Associazione Italiana per la Ricerca sul CancroI and European Union Sixth Framework Program (MUGEC:LSHG-CT-2005-005203). P.C., R.C., and D.C. received fellowships from ART. L.C. was a recipient of a fellowship in memory of Dr. Cesare Girola.
2 Address correspondence and reprint requests to Dr. Marina Noris, Mario Negri Institute for Pharmacological Research, via Camozzi 3, 24020 Ranica, Bergamo, Italy. E-mail address: noris{at}marionegri.it
3 Abbreviations used in this paper: I/R, ischemia/reperfusion; TIR8/Tir8, TLR/IL-1 receptor 8; DC, dendritic cell; BUN, blood urea nitrogen; FoxP3, forkhead box P3; Treg, regulatory T cell; HA, hyaluronic acid; Teff, effector T cell; HAS-1, hyaluronan synthase 1; MHCII, MHC class II; AU, arbitrary unit.
4 The online version of this article contains supplemental material.
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