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.

Where’s Waldo? Extrahepatic Site Options for Islet Transplantation

“…Endoscopic access provides a novel approach to placing and surveying the islets. Transendoscopic gastric submucosa islet allotransplantion in diabetic pigs had similar reduction in baseline glucose and insulin requirements as those with laparoscopically placed gastric islet transplants [69,74]. Minimal C peptide was seen 60 minutes after transplant, suggesting minimal islet loss.…”

The Spleen as an Optimal Site for Islet Transplantation and a Source of Mesenchymal Stem Cells

“…The submucosal space of the gastrointestinal tract is also a possible transplant site, with a rich vascular supply providing oxygen and nutrients, and which connects to the same portal system as the liver, spleen and pancreas [ 55 ]. Although Hara and colleagues studied transplantation into this location by endoscopy in a pig model [ 29 , 62 ], there have been limited demonstrations of this concept in large animal models.…”

Spleen, as an Optimal Site for Islet Transplantation and a Source of Mesenchymal Stem Cells

“…The submucosal space of the gastrointestinal tract is another candidate site that has a rich vascular supply providing oxygen and nutrients and connects to the same portal system as the liver, spleen and pancreas [53]. Hara and colleagues have studied transplantation into this location by endoscopy in a pig model [27,60], but there has been limited demonstration of this concept in large animal models. The brain, testis, the anterior to chamber of the eye, and the thymus are the organs where the immunological response is suppressed and are thus considered "immune privileged" sites.…”