Long-Term Follow-Up of the Edmonton Protocol of Islet Transplantation in the United States

Abstract

We report the long‐term follow‐up of the efficacy and safety of islet transplantation in seven type 1 diabetic subjects from the United States enrolled in the multicenter international Edmonton Protocol who had persistent islet function after completion of the Edmonton Protocol. Subjects were followed up to 12 years with serial testing for sustained islet allograft function as measured by C‐peptide. All seven subjects demonstrated continued islet function longer than a decade from the time of first islet transplantation. One subject remained insulin independent without the need for diabetic medications or supplemental transplants. One subject who was insulin‐independent for over 8 years experienced graft failure 10.9 years after the first islet transplant. The remaining six subjects demonstrated continued islet function upon trial completion, although three had received a supplemental islet transplant each. At trial completion, five subjects were receiving insulin and two remained insulin independent, although one was treated with liraglutide. The median hemoglobin A1c was 6.3% (45 mmol/mol). All subjects experienced progressive decline in the C‐peptide/glucose ratio. No patients experienced severe hypoglycemia, opportunistic infection, or lymphoma. Thus, although the rate and duration of insulin independence was low, the Edmonton Protocol was safe in the long term. Alternative approaches to islet transplantation are under investigation.

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

“…Opsonization by these antibodies onto the islets, which experiments have shown are permeable to certain alginate microcapsules with unconventionally large pores, can activate complement proteins such as C3 and C4, which may produce cytotoxic effects on the encapsulated islets [ 53 , 56 ]. As the above mechanisms of rejection pertain solely to NPCCs, antigens other than Gal α- [1,3] gal, a nonspecifi c antigen in most mammalian species, are likely responsible for the activation of the adaptive immune response seen in immunocompetent mouse recipients. Unfortunately, humans are the only mammalian species lacking expression of gal α- [1,3] gal, and therefore, the only species prone to mount a response upon detection of this epitope that is ubiquitous in porcine islets.…”

“…As the above mechanisms of rejection pertain solely to NPCCs, antigens other than Gal α- [1,3] gal, a nonspecifi c antigen in most mammalian species, are likely responsible for the activation of the adaptive immune response seen in immunocompetent mouse recipients. Unfortunately, humans are the only mammalian species lacking expression of gal α- [1,3] gal, and therefore, the only species prone to mount a response upon detection of this epitope that is ubiquitous in porcine islets.…”

“…Therefore, they are economically ineffi cient to harvest, isolate and culture compared to FP ICCs and neonatal islets. Like neonatal islets, adult porcine islets express gal alpha [1,3] gal antigens, albeit to a signifi cantly lesser extent [ 43 ]. Consequently, anti-gal antibodies present in human sera are responsible for the lysis of exposed neonatal islet cells, but have a diminished role in the eradication of incompletely encapsulated adult islets [ 74 ].…”

“…With appropriate immunosuppression regimens, patients that are able to remain insulin independent for up to 8 years post-transplant [ 1 ]. Unfortunately, a scarcity of donor organs, low islet yields after isolation, graft destruction due to the instant bloodmediated infl ammatory reaction [IBMIR] and graft dysfunction due to concomitant immunosuppressive therapy impede further progress.…”

La thérapie cellulaire du diabète

“…Le consortium de transplantation d'îlots (CIT) a établi un registre qui permet de documenter les conditions et l'évolution des greffes cliniques : selon une étude rétrospective récente [7], la plupart des patients reçoivent actuellement un régime immunosuppresseur qui associe des anticorps anti-lymphocytes T et des inhibiteurs du TNFα (tumor necrosis factor α) pour l'induction, et des inhibiteurs de la calcineurine et de mTOR (mammalian target of rapamycin) pour la maintenance, en post-greffe. Ces nouveaux protocoles pourraient avoir un impact important sur la survie à long terme des greffons comme en témoigne l'étude de suivi des patients EXIIST (extended immunosuppression in islet transplantation -ITN040CT) [8] qui montre, chez sept patients traités au long cours (avec le tacrolimus associé au sirolimus ou mycofenolate mofetil), la persistance d'une fonction des îlots jusqu'à 10,9 ans post-greffe, avec un impact positif sur le contrôle glycémique (HbA1 C moyenne = 6,3%). Globalement, ces patients sont restés insulino-indépendants pendant 54 mois après transplantation sans rencontrer d'effets secondaires majeurs.…”