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Presenter: M., Cowley, Sydney, Australia
Authors: M. Cowley, A. Weinberg, S. Walters, W. Hawthorne, J. Gunton, T. Loudovaris, P. O’Connell, S.T. Grey
Human islets express a marked pro-inflammatory molecular signature prior to transplantation
M. Cowley1, A. Weinberg1, S. Walters1, W. Hawthorne1, J. Gunton1, T. Loudovaris2, P. O’Connell3, S.T. Grey1
1 Garvan Institute, Immunology, Sydney, Australia; 2 St Vincent's Institute, Fitzroy, Australia; 3 Westmead Hospital, Westmead, Australia
Objective: In the context of islet transplantation, experimental models showthat induction of islet intrinsic NF-κB-dependent pro-inflammatory genes cancontribute to islet graft rejection. Isolation of human islets triggersactivation of the NF-κB and mitogen-activated kinase (MAPK) stress responsepathways. However, the down stream NF-κB-target genes induced in human isletsduring the isolation process are poorly described.
Methods: Therefore in this study,using microarray and RTqPCR approaches, we determined the pattern of genesexpressed by a set of 15 human islet preparations.
Results: We found that isolated humanislets express a panel of genes reminiscent of cells undergoing a marked NF- k B-dependentpro-inflammatory response. Induced genes included; matrix metallopeptidase 1 (MMP1) andFibronectin 1 (FN1), factors involved in tissue remodelling, adhesion and cellmigration; cytokines, including IL-1 b and IL-8; A20and ATF3, genes regulating cell survival; and notably a set of chemokines thatwould favour the recruitment of neutrophils and monocytes, including CXCL2,CCL2, CXCL12, CXCL1, CXCL6, CCL28.
Conclusions: These data show that human islets can make cell autonomouscontributions to the ensuing allograft response; which may act to exacerbatethe anti-islet-graft immune response. These data highlight the potentialimportance of islet intrinsic pro-inflammatory responses as targets for therapeuticintervention.
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