Immunoregulatory Function of IL-27 and TGF-β1 in Cardiac Allograft Transplantation |
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Authors: | Laetitia Le Texier Pamela Thebault Manuela Carvalho-Gaspar Virginie Vignard Emmanuel Merieau Claire Usal Maria-Cristina Cuturi Kathryn J Wood Elise Chiffoleau |
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Institution: | 1 Institut National de la Santé Et de la Recherche Médicale, U1064, Nantes, France. 2 Centre Hospitalier Universitaire de Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Institut Urologie Néphrologie, Nantes, France. 3 Université de Nantes, Faculté de Médecine, Nantes, France. 4 Currently, Centre de Recherche de l'H?pital Maisonneuve-Rosemont, Montréal, Quebec, Canada. 5 Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom. |
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Abstract: | BACKGROUND: Deciphering the mechanisms of tolerance represents a crucial aim of research in transplantation. We previously identified by DNA chip interleukin (IL)-27 p28 and transforming growth factor (TGF)-β1 as overexpressed in a model of rat cardiac allograft tolerance mediated by regulatory CD4CD25 T cells. The role of these two molecules on the control of the inflammatory response remains controversial. However, both are involved in the regulation of the T helper 17/Treg axis, suggesting their involvement in tolerance. METHODS: We analyzed regulation of IL-27 and TGF-β1 expression in allograft response and their role in tolerance by using blocking anti-TGF-β antibody and by generating an adeno-associated virus encoding IL-27. RESULTS: Here, we confirmed the overexpression of IL-27 and TGF-β1 in tolerated cardiac allografts in two different rodent models. We observed that their expression correlates with inhibition of T helper 17 differentiation and with expansion of regulatory CD4CD25 T cells. We showed in a rat model that anti-TGF-β treatment abrogates infectious tolerance mediated by the transfer of regulatory CD4CD25 T cells. Moreover, overexpression of IL-27 by adeno-associated virus administration in combination with a short-term immunosuppression allows prolongation of cardiac allograft survival and one tolerant recipient. We found that IL-27 overexpression did not induce Foxp3CD4CD25 T-cell expansion but rather IL-10-expressing CD4 T cells in the tolerant recipient. CONCLUSIONS: Taken together, these data suggest that both TGF-β1 and IL-27 play a role in the mechanisms of tolerance. However, in contrast to TGF-β1, IL-27 seems not to be involved in regulatory CD4CD25 T-cell expansion but rather in their mode of action. |
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