Islet-Expressed CXCL10 Promotes Autoimmune Destruction of Islet Isografts in Mice With Type 1 Diabetes

Christine Bender, Selina Christen, Klaus Scholich, Monika Bayer, Josef M. Pfeilschifter, Edith Hintermann, Urs Christen
2016 Diabetes  
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing b-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
more » ... V mice expressing a lymphocytic choriomeningitis virus (LCMV) protein in the b-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. Treatment of type 1 diabetes (T1D) with exogenous insulin is life saving but cannot completely prevent secondary complications. At the beginning of this millennium, the transplantation of islets of Langerhans had become a huge hope for patients with diabetes, and several clinical trials have been conducted since. It provides T1D patients with functional islets, resulting in a more stable glycemic control than that achieved with exogenous insulin therapy and, thereby, avoids severe hypoglycemia and finally reduces long-term complications (1). Most clinical trials followed the "Edmonton Protocol," according to which purified islets are injected into hepatic portal vein, settle in the liver, and start insulin production (2). A multicenter trial in North-America and Europe (3) that followed the Edmonton Protocol has confirmed that islet transplantation was indeed successful in establishing insulin independence. After the initial drawback, during which most subjects lost insulin independence within a year (3), and long-term function of the islet grafts could be neither guaranteed nor predicted (4), in subsequent clinical trials (5) the rate of insulin independence 3 years after undergoing transplantation has gradually increased from 27% (years 1999-2002) up to 44% (years 2007-2010). Further, a recent long-term follow-up study (6) in the U.S. demonstrated continued islet function in all seven patients for more than 10 years. An aggressive corticosteroid regimen has been replaced with a combination of milder immunosuppressive drugs, such as sirolimus, tacrolimus, and daclizumab, but many side effects of immunosuppression, such as neutropenia, pneumonia, mouth ulcerations, fever, and worsening genital herpes, still persist (3). The decreased rejection rate observed in the last few years can be attributed partly to changes in
doi:10.2337/db16-0547 pmid:27797910 fatcat:jtd6uckuxzdl7cacaq5rpk62ly