Progress in Clinical Encapsulated Islet Xenotransplantation

Abstract

At the 2015 combined congress of the Cell Transplant Society, International Pancreas and Islet Transplant Association, and International Xenotransplantation Association, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics - (1) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (2) the inflammatory response to encapsulated pig islets, (3) methods to improve the secretion of insulin by pig islets, (4) genetic modifications to the islet-source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (5) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (1) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (2) the development of a more biocompatible capsule and/or the minimization of a foreign body reaction; (3) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (4) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally harmonized ethical and regulatory framework.

Figure 1. Proposed schema of the early inflammatory reaction following the transplantation of microencapsulated pig islets into the peritoneal cavity of the mouse

Transplanted microencapsulated islets are damaged by hypoxia and/or inadequate nutrients as well as by the inflammatory reaction occurring against the microcapsules themselves. Damaged islets then release HMGB1, which stimulates the accumulation of mononuclear cells and induces further inflammation, leading to graft loss. Blockade of these inflammatory pathways improves the outcome of microencapsulated pig islet transplantation in a mouse model.

Figure 2. Comparison of glucose-induced insulin secretion from perifused pig (●) and human (○) islets

Batches of 200–600 islets were perifused in Krebs medium containing 1 mM glucose (G1) then 15 mM glucose (G15) as indicated at the top of the figure. Insulin secretion was then measured in the effluent fractions. Numbers along the curves indicate stimulation index during first [2–8 min] and second [10–30 min] phases. Values are means ± SEM for n=3–4 from 4 different preparations.

Figure 3. Insulin secretion from isolated pig islets

Neonatal (A) and adult (B) isolated islets were exposed to 200 MOI viral expression vector carrying sequences coding for glucagon-like peptide-1 and activated muscarinic receptor type 3 for 48 hours. Batches of 200 islets were incubated for 2 hours in 1 ml Krebs medium containing 1 mM glucose (G1) or 15 mM glucose (G15). Insulin secretion was measured in the incubation media and expressed as a percentage of total insulin content of each batch of islets. Numbers above pairs of columns indicate G15/G1 stimulation index (* p<0.05). Values are means ± SEM for n=38–46 from 10 different neonatal preparations and n=40–50 from 11 different adult preparations.