Pancreatic Islet Transplantation Using the Nonhuman Primate (Rhesus) Model Predicts That the Portal Vein Is Superior to the Celiac Artery as the Islet Infusion Site

Abstract

We've established a nonhuman primate islet allotransplant model to address questions such as whether transplanting islets into the gut's arterial system would more safely and as effectively support long-term islet allograft survival compared with the traditional portal vein approach. We reasoned that islets make up <2% of pancreatic cell mass but consume an estimated 20% of arterial blood flow, suggesting an advantage for the arterial site. Access to the arterial system is also easier and safer than the portal system. Pancreatectomized rhesus macaques were transplanted with allogeneic islets infused into either the portal vein (n ‫؍‬ 6) or the celiac artery (n ‫؍‬ 4). To prevent rejection, primates were given daclizumab, tacrolimus, and rapamycin. In five of six portal vein experiments, animals achieved normoglycemia without exogenous insulin. In contrast, none of the animals given intra-arterial islets showed even transient insulin independence (P ‫؍‬ 0.048). Two of the latter animals received a second islet transplant, this time to the portal system, and both achieved insulin independence. Thus, intraportal islet transplantation under conventional immunosuppression is feasible in primates and can result in long-term insulin independence when adequate immunosuppression is maintained. Arterial islet injection, however, does not appear to be a viable islet transplantation technique. Diabetes 51:2135-2140, 2002 T ype 1 diabetes results from the immune-mediated destruction of the insulin-producing pancreatic ␤-cells, located in cell clusters called the islets of Langerhans (1,2). The field of islet transplantation recently emerged as a promising way to restore patients with type 1 diabetes to insulin independence (3-5). Before islet transplantation can be developed as a clinically viable treatment for type 1 diabetes, however, important issues need be addressed. These include formulating guidelines to predict an appropriate islet dose, identifying reliable markers of islet quality, generating a renewable islet source, determining the best islet infusion site, promoting islet viability and growth, and improving ways to monitor and prevent rejection. We reasoned that many of these questions could best be addressed using a preclinical nonhuman primate model. Nonhuman primates are highly relevant because of their phylogenetic relationship to humans (6) and because many of the newer immunomodulatory agents (antibodies and receptor fusion proteins) are specific for human epitopes, many of which cross-react with the corresponding primate epitopes. (5,7,8).We sought to establish a nonhuman primate model to closely mimic a recently reported steroid-sparing regimen (5,9). Currently, isolated islets are transplanted in the clinical setting via a catheter percutaneously placed into the recipient's portal vein to the liver (5). We asked whether transplanting islets to an arterial bed (e.g., the celiac tree) versus the portal vein would more safely and as effectively support long-term islet allograft survival. We reasoned that b...

Positron Emission Tomography in Clinical Islet Transplantation

“…Little is known about the magnitude of these damaging forces in the portal vein. In a study in which isolated islets were injected into the hepatic artery in nonhuman primates, no remaining islets could be found in the liver, nor could any C-peptide be detected (31 …”

Endovascular Methods for Stem Cell Transplantation

“…Further, not all cells are optimal for intra-luminal transplantation. It is, for example, known that insulin producing cells lack the capability to perform diapedesis (Hirshberg et al 2002) and we show that hNPC, a cell system previously transplanted by open surgical means (Wennersten et al 2004) also lacks the capability to perform diapedesis. For these cell systems, and other applications, we have developed the Extroducer as a tool to establish a direct, minimal invasive working channel with parenchymal access in organs that are difficult or risky to reach with traditional techniques.…”

“…Finally, both our own findings regarding hNPCs and other previously known cells incapable of diapedesis, such as insulin producing cells (Hirshberg et al 2002), shows the apparent need for surgical techniques. In some organs that are hard to reach and/or when surgical technique comes with a high risk of adverse events for the patients, the need for an alternative strategy becomes apparent.…”

“…It has been shown that when performing transplantations to a rodent stroke model and comparing intravenous, intra-ventricular and intra-striatal injections, the highest efficacy in sheer number of cells were obtained with the intra-striatal route (Jin et al 2005). Further limiting the selective intra-luminal approach is the speculation that some cell systems, such as insulin producing cells, appear incapable of leaving the bloodstream (Hirshberg et al 2002). In all implementations aimed at intra-luminal administration (intra-luminal encompassing both intravenous and selective intra-arterial administration) the ability of the cells to leave the bloodstream, or perform diapedesis ) is fundamental.…”

“…As previously mentioned, in a diverging literature, it has been speculated that some cells totally lack the function of exiting the blood stream, thereby limiting intra-luminal based techniques. Even though insulin producing cells appears incapable of leaving the bloodstream, they are still transplanted through the portal vein (Hirshberg et al 2002). The mechanism of action is believed to be microembolization of the cells to the liver parenchyma in the low pressure system that the portal vein constitutes (Lehmann et al 2007).…”