832 Successful human-to-nonhuman primate pancreatic islet intraportal xenotransplantation using a human allo-based immunosuppression regimen
Wednesday November 18, 2015 from 15:30 to 17:00
Room 111-112

James J McGarrigle, United States

Research Assistant Professor


University of Illinois at Chicago


Successful human-to-nonhuman primate pancreatic islet intraportal xenotransplantation using a human allo-based immunosuppression regimen

James McGarrigle1, Matthew A Bochenek1,2, Enza Marchese1, Arshad Khan1, Diana Gutierrez1,2, Augusta Mikalauskaite1, Benjamin McCracken1, Mick Reedy1, Mustafa Omami1, Chun-Chieh Yeh1, Mohammad Nourmohammadzadeh1,2, Ling-jia Wang1, Joshua Mendoza-Elias1,2, Yong Wang1, Jose Oberholzer1,2.

1Surgery, University of Illinois at Chicago, Chicago, IL, United States; 2Bioengineering, University of Illinois at Chicago, Chicago, IL, United States

Intraportal pancreatic islet cell transplantation is a successful treatment for type-1 diabetes (T1DM) in humans. Unfortunately, the lack of donor pancreatic organs is a major limitation to this therapy. As the scientific community nears towards the production of “islet like”, human derived β-cell sources; it has become increasingly evident that rigorous, pre-clinical, in vivo evaluation of such β-cell types is imperative prior to clinical trials. The gold standard large animal model for preclinical testing is the non-human primate (NHP). However, the major challenge to successful human to NHP pancreatic islet xenotransplantation is the detrimental effects of the hosts’ response to transplanted foreign tissue. In particular the immediate loss of islets by the instant blood-mediated inflammatory reaction (IBMIR) as well as ongoing humoral and cell-mediated immune responses led by T and B lymphocytes. In order to investigate specific parameters of immunosuppression required to protect human derived tissue from rejection in NHP, a human allo-based immunosuppressive drug regimen (sirolimus, tacrolimus, etanrecept and basiliximab cocktail) was tested using a cynomolgus monkey model. In this study, we successfully performed intraportal human islet cell transplantation into a streptozotocin induced diabetic cynomolgus monkey. The animal commenced immunosuppression on the day of islet infusion. For a period of approximately 1 month post-transplantation, there was a significant reduction in the daily exogenous insulin requirements compared to pre-transplantation levels. Pre-transplant average insulin required: 3.85 units daily:  average recorded daily blood glucose levels: 355 ± 184 mg/dL. Thirty days post transplant average insulin required: 1.03 units daily; average recorded daily blood glucose levels 196 ± 57 mg/dL. Furthermore, C-peptide was detected for up to one-month post transplantation and hemoglobin A1c levels were significantly reduced after one month (7.1% to 5.5%). Histological analysis of liver biopsies retrieved from the host at 7 days and 30 days post transplantation indicated varying degrees of IBMIR. However, signs of aggressive rejection or cellular infiltration were not observed, and islet cells stained positive for all three major islet hormones; insulin, glucagon and somatostatin at 30 days. This is the first reported successful intraportal xenotransplantation of naked human islet cells into a cynomologus monkey model, and indicates the potential to use human allo-based immunosuppressive drugs without the need for more intensive immunosuppressive drugs that are usually required for xenotransplantation in the NHP model. 

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