title: Islet-Expressed CXCL10 Promotes Autoimmune Destruction of Islet Isografts in Mice With Type 1 Diabetes.
abstract: Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β-cells in the pancreas. Thereby, the chemokine CXC-motif ligand 10 (CXCL10) plays an important role in the recruitment of autoaggressive lymphocytes to the islets of Langerhans. Transplantation of isolated islets as a promising therapy for T1D has been hampered by early graft rejection. Here, we investigated the influence of CXCL10 on the autoimmune destruction of islet isografts using RIP-LCMV mice expressing a lymphocytic choriomeningitis virus (LCMV) protein in the β-cells. RIP-LCMV islets express CXCL10 after isolation and maintain CXCL10 production after engraftment. Thus, we isolated islets from either normal or CXCL10-deficient RIP-LCMV mice and transferred them under the kidney capsule of diabetic RIP-LCMV mice. We found that the autoimmune destruction of CXCL10-deficient islet isografts was significantly reduced. The autoimmune destruction was also diminished in mice administered with an anti-CXCL10 antibody. The persistent protection from autoimmune destruction was paralleled by an increase in FoxP3+regulatory T cells within the cellular infiltrates around the islet isografts. Consequently, CXCL10 might influence the cellular composition locally in the islet graft, thereby playing a role in the autoimmune destruction. CXCL10 might therefore constitute a potential therapeutic target to prolong islet graft survival.
authors: Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany.
authors: Christine
authors: C
authors: Bender
authors: Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany.
authors: Selina
authors: S
authors: Christen
authors: Institute for Clinical Pharmacology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany.
authors: Klaus
authors: K
authors: Scholich
authors: Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany.
authors: Monika
authors: M
authors: Bayer
authors: Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany.
authors: Josef M
authors: JM
authors: Pfeilschifter
authors: Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany.
authors: Edith
authors: E
authors: Hintermann
authors: Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany christen@med.uni-frankfurt.de.
authors: Urs
authors: http://orcid.org/0000-0003-4165-7976
authors: U
authors: Christen
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000235:genetics; D006085:Graft Survival / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D064596:Isografts / Q000378:metabolism*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains
chemical_list: D054357:Chemokine CXCL10