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Increased Number of Islet-Associated Macrophages in Type 2 Diabetes Jan A. Ehses 1 , Aurel Perren 2 , Elisabeth Eppler 3 , Pascale Ribaux 4 , John A. Pospisilik 5 , Ranit Maor-Cahn 1 , Xavier Gueripel 2 , Helga Ellingsgaard 1 , Marten K.J. Schneider 6 , Gregoire Biollaz 7 , Adriano Fontana 7 , Manfred Reinecke 3 , Francoise Homo-Delarche 8 and Marc Y. Donath 1 1 Division of Endocrinology and Diabetes and Center for Integrated Human Physiology, University Hospital of Zürich, Zürich, Switzerland 2 Department of Pathology, University Hospital of Zürich, Zürich, Switzerland 3 Division of Neuroendocrinology, Institute of Anatomy, University of Zürich, Zürich, Switzerland 4 Department of Genetic Medicine and Development, University Medical Center, Geneva, Switzerland 5 Institute of Molecular Biotechnology, Austrian Academy of Science, Vienna, Austria 6 Laboratory for Transplantation Immunology, University Hospital of Zürich, Zürich, Switzerland 7 Division of Clinical Immunology, University Hospital of Zürich, Zürich, Switzerland 8 Unité mixte de recherches 7059, National Center for Scientific Research, Paris 7 University/D. Diderot, Paris, France Address correspondence and reprint requests to Dr. Jan A. Ehses, Division of Endocrinology and Diabetes, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland. E-mail: jan.ehses{at}usz.ch . Or to Dr. Marc Y. Donath, Division of Endocrinology and Diabetes, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland. E-mail: marc.donath{at}usz.ch Abstract Activation of the innate immune system in obesity is a risk factor for the development of type 2 diabetes. The aim of the current study was to investigate the notion that increased numbers of macrophages exist in the islets of type 2 diabetes patients and that this may be explained by a dysregulation of islet-derived inflammatory factors. Increased islet-associated immune cells were observed in human type 2 diabetic patients, high-fat–fed C57BL/6J mice, the GK rat, and the db/db mouse. When cultured islets were exposed to a type 2 diabetic milieu or when islets were isolated from high-fat–fed mice, increased islet-derived inflammatory factors were produced and released, including interleukin (IL)-6, IL-8, chemokine KC, granulocyte colony-stimulating factor, and macrophage inflammatory protein 1α. The specificity of this response was investigated by direct comparison to nonislet pancreatic tissue and β-cell lines and was not mimicked by the induction of islet cell death. Further, this inflammatory response was found to be biologically functional, as conditioned medium from human islets exposed to a type 2 diabetic milieu could induce increased migration of monocytes and neutrophils. This migration was blocked by IL-8 neutralization, and IL-8 was localized to the human pancreatic α-cell. Therefore, islet-derived inflammatory factors are regulated by a type 2 diabetic milieu and may contribute to the macrophage infiltration of pancreatic islets that we observe in type 2 diabetes. AEC, 3-amino-9-ethylcarbazole ECM, extracellular matrix FITC, fluorescein isothiocyanate G-CSF, granulocyte colony-stimulating factor IL, interleukin IP-10, interferon-inducible protein 10 MHC, major histocompatibility complex MIP, macrophage inflammatory protein Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 19 June 2007. DOI: 10.2337/db06-1650. 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. Accepted May 21, 2007. Received November 26, 2006. DIABETES

Recruitment of human NK cells to porcine tissues has been demonstrated in pig organs perfused ex vivo with human blood in the early 1990s. Subsequently, the molecular mechanisms leading to adhesion and cytotoxicity in human NK cell-porcine endothelial cell (pEC) interactions have been elucidated in vitro to identify targets for therapeutic interventions. Specific molecular strategies to overcome human anti-pig NK cell responses include (1) blocking of the molecular events leading to recruitment (chemotaxis, adhesion, and transmigration), (2) expression of human MHC class I molecules on pECs that inhibit NK cells, and (3) elimination or blocking of pig ligands for activating human NK receptors. The potential of cell-based strategies including tolerogenic dendritic cells (DC) and regulatory T cells (Treg) and the latest progress using transgenic pigs genetically modified to reduce xenogeneic NK cell responses are discussed. Finally, we present the status of phenotypic and functional characterization of nonhuman primate (NHP) NK cells, essential for studying their role in xenograft rejection using preclinical pig-to-NHP models, and summarize key advances and important perspectives for future research.

Background: In immunocompromised patients, human cytomegalovirus (HCMV) infection is a major cause of morbidity and mortality. Suppressor of cytokine signaling (SOCS) proteins are very potent negative regulators of the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. We hypothesized that HCMV exploits SOCS1 and/or SOCS3 to its advantage. Methods: All experiments were carried out with primary human lung-derived microvascular endothelial cells (HMVEC). SOCS1 and SOCS3 were silenced by transfecting the cells with siRNA. HCMV was propagated and titered on human lung-derived fibroblasts MRC5. Real-time PCR and Western blot were used to detect mRNA and protein levels, respectively. Results: The data presented show that an efficient replication of HCMV in HMVEC is dependent on SOCS3 protein. Time course analysis revealed an increase in SOCS3 protein levels in infected cells. Silencing of SOCS3 (siSOCS3) resulted in inhibition of viral immediate early, early, and late antigen production. Consistently, HCMV titers produced by siSOCS3 cultures were significantly decreased when compared to control transfected cultures (siCNTRs). STAT1 and STAT2 phosphorylation was increased in siSOCS3-infected cells when compared to siCNTR-treated cells. Conclusion: These findings indicate the implication of SOCS3 in the mechanism of HCMV-mediated control of cellular immune responses.