Anti-inflammatory thalidomide improves islet grafts survival and functions in a xenogenic environment

• Published in: PloS one 2009-07, Vol.4 (7), p.e6312
• Main Authors: Chen, Chunguang, Kuehn, Carina, Bretzel, Reinhard G, Linn, Thomas
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - pharmacology; Apoptosis; Blood Glucose - analysis; Cell growth; Diabetes; Diabetes and Endocrinology/Type 1 Diabetes; Endothelium; Experiments; Glucose; Graft rejection; Grafting; Grafts; House mouse; Immunology/Immune Response; Infiltration; Inflammation; Islet cells; Islets of Langerhans - drug effects; Islets of Langerhans - pathology; Kidneys; Kinases; Mice; Mice, Inbred C57BL; Pancreatic islet transplantation; Permeability; Pharmacology/Drug Development; Phosphates; Rodents; Sphingosine; Sphingosine 1-phosphate; Survival; Swine; Thalidomide; Thalidomide - pharmacology; TNF inhibitors; Transplantation; Transplantation, Heterologous; Transplants & implants; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0006312

Thalidomide possesses both anti-inflammatory and anti-angiogenic properties. This study investigates its potential application in islet transplantation with a xenogenic transplantation model. Transplantation was performed using C57Bl/6 mice and NMRI nu/nu mice as recipients of porcine islets. Moreover, islet graft vasculature and inflammation were investigated to identify the mechanisms of thalidomide action. In the immunocompetent environment of C57Bl/6 mice, a fast graft rejection was observed. The group treated with thalidomide 200 mg/kg BW per day achieved and maintained euglycemia in the complete observation period for 42 days. The treated mice had more functional islet graft mass with less leukocyte infiltration. The pro-inflammatory TNF-alpha and VEGF content in islet grafted kidneys was significantly lowered by the treatment. By comparison, thalidomide was not effective in improving graft survival in immunocompromised nude mice. It strongly inhibited the VEGF and TNF-alpha-induced endothelial proliferation of isolated pig islets in a dose dependent manner. The magnitude of thalidomide's inhibitory effect was nearly identical to the effect of VEGF- receptor 2 inhibitor SU416 and anti-TNF-receptor 1 neutralizing antibody, and was reversed by sphingosine-1-phosphate. In conclusion, the anti-inflammatory effect of thalidomide improved islet graft survival and function in a transplantation model with a maximum immune barrier.