lslet cell department
Baylor Research institute
Targeting islet-derived IFN-gamma-inducible Protein 10 (IP-10/CXCL10) to prevent early innate immune destruction of islet grafts
Gumpei Yoshimatsu1, Mazhar A Kanak2, Morihito Takita1, Charles Chang2, Omar Khan1, Rauf Shahbazov1, Marlon F Levy3, Michael C Lawrence1, Bashoo Naziruddin3.
1Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, United States; 2Institute of Biomedical Studies, Baylor University, Waco, TX, United States; 3Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, United States
Introduction: Early loss of pancreatic islet graft mass occurs within hours of transplantation. This significant loss of islet cells is attributed the immediate blood-mediated inflammatory reaction (IBMIR) occurring after intraportal infusion that is characterized by activation of thromboinflammatory events and secretion of proinflammatory chemokines and cytokines. We hypothesized that stressed islets secrete the chemokine C-X-C motif ligand 10 or IFN-gamma-inducible protein 10 (CXCL10/IP-10) which induces the innate inflammatory component of IBMIR. Therefore, blockade of IP-10 might improve islet graft function.
Methods: We analyzed the role of IP-10 in islet autograft function in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT) and in animal models utilizing C57BL/6 IP10-/- transgenic mice. Serum samples collected from 26 TPIAT patients within 24 h after islet infusion were analyzed for IP-10 using Luminex assay. Patients were divided into low (n=15) and high (n=11) post-transplant IP-10 plasma concentration determined by the area under the curve (AUC) after correction of islet yield (IEQ). For animal models, a marginal dose of 200 islets isolated from IP10-/- knockout C57BL/6 mice were transplanted intraportally to wild-type STZ-diabetic C57BL/6 mice and neutralizing anti-IP-10 antibody was delivered to wild-type STZ-diabetic mice receiving a marginal intraportal dose of islets. Graft function was analyzed by blood glucose profiling.
Results: TPIAT patients expressing low blood serum levels of IP-10 had significantly higher levels of secreted C-peptide compared to patients expressing high levels of IP-10 after 1 year post-transplantation (1.1 ± 0.2 vs 0.5 ± 0.1ng/mL; p<0.05). In the animal study, wild type mice receiving islets intraportally from IP10-/- knockout donor mice showed significant improvement in blood glucose concentration profiles up to 30 days post-transplantation (Figure1).
Conclusion: The present study indicated that IP-10 produced from islets during the peritransplant period results in early loss of islet graft function and that blocking IP-10 with a neutralizing antibody can improve glycemic control.
Yoshiko Tamura. Ana Rahman. Nofit Borenstein. Baylor Health Care System.
15:30 - 17:00
|Modifying Islet Immunity - Adaptive, Innate, and Xenoimmunity||Targeting islet-derived IFN-gamma-inducible Protein 10 (IP-10/CXCL10) to prevent early innate immune destruction of islet grafts||Plenary Room 1|
17:30 - 18:30
|Joint Poster Session||Pancreas derived mesenchymal stem cell improve the glucose response of transplanted islets more effectively than adipose tissue derived stem cells||Main Foyer 1 & 2|