Endoscopic biopsy of islet transplants in the gastric submucosal space provides evidence of islet graft rejection in diabetic pigs

ABSTRACT

Transplantation of islets into the gastric submucosal space (GSMS) has several advantages (e.g., avoidance of the instant blood-mediated inflammatory response [IBMIR], ability to biopsy). The aim of this study was to determine whether endoscopic biopsy of islet allografts transplanted into the GSMS in diabetic pigs can provide histopathological and immunohistochemical information that correlates with the clinical course (e.g.,, blood glucose level, insulin requirement). Islet allografts (Group1: 10,000 kIEq /kg [n = 4]; Group2: 15,000 kIEq /kg [n = 2]) were transplanted into the GSMS of diabetic pigs under immunosuppression. In Group2, the anti-oxidant, BMX-001 was applied during preservation, isolation, and culture of the islets, and at the time of transplantation. Endoscopic biopsies of the islet grafts were obtained one or 2 weeks after transplantation, and histopathological features were compared with the clinical course (e.g., blood glucose, insulin requirement). In Group1, in the absence of anti-oxidant therapy, most of the islets became fragmented, and there was no reduction in exogenous insulin requirement. In Group2, with an increased number of transplanted islets in the presence of BMX-001, more healthy insulin-positive islet masses were obtained at biopsy and necropsy (4 weeks), and these correlated with reductions in both blood glucose level and insulin requirement. In all cases, inflammatory cell infiltrates were present. After islet transplantation into the GSMS, endoscopic biopsy can provide information on graft rejection, which would be an immense advantage in clinical islet transplantation.

KEYWORDS:

• anti-oxidant
• biopsy
• endoscopy
• gastric submucosal space
• islets
• islets
• pig
• transplantation

Abbreviations

GSMS	=	gastric submucosal space
IBMIR	=	instant blood-mediated inflammatory reaction
PBMC	=	peripheral blood mononuclear cell
STZ	=	streptozotocin.

Disclosure of potential conflicts of interest

Jon D Piganelli is a consultant for BioMimetix Pharmaceutical, Inc. No other authors have a conflict of interest.

Acknowledgements

The authors thank Mr. Masahiro Ashizuka (Olympus Corporation of the Americas) for his technical help in performing endoscopic islet transplantation and biopsy.

Funding

This study was supported by NIH grant RO3 (AI096296, HH), by The Uehara Memorial Foundation Postdoctoral Fellowship (TT), by The Mochida Memorial Foundation for Medical and Pharmaceutical Research (TT), by Kawasaki Sukenobu Memorial Fund of Kawasaki Medical School for Research Study (MF), by Kawasaki Medical School Alumni Association Fund for Foreign Study (MF), and by an Ocular Tissue Engineering and Regenerative Ophthalmology Postdoctoral Fellowship (WL).