Islet cell xenotransplantation: a serious look toward the clinic

Abstract

Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near-physiologic function and yearlong survival in clinically relevant pig to primate model systems. These proof-of-concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this commentary, we examine recent progress in islet xenotransplantation, with a critical eye towards the gaps between the current state of the art and the state required for appropriate clinical investigation.

Clinical implementation of islet transplantation: A current assessment

“…We, and other groups, have shown long‐term islet function of transgenic porcine islets in diabetic immunosuppressed monkeys (Fig. ), further confirming that genetically engineering of animal tissues contributes to successful engraftment and, once key xenorejection pathways are identified and neutralized, that animal tissue performs in xenogeneic environments without the need for heavy immunosuppression . One of the consequences of improving compatibility between donor and recipient will translate to lower islet mass required to achieve glucose control after transplantation.…”

Early barriers to neonatal porcine islet engraftment in a dual transplant model

“…Although results in preclinical long-term function of porcine islet xenografts by various groups have been promising, it is important to note that these studies with experimental agents remain outside the realm of clinical application. (18) We sought to compare islet allografts and xenografts at one week after transplantation based on this regimen due to our prior experience with successful GTKO engraftment.…”

Dual Islet Transplantation Modeling of the Instant Blood-Mediated Inflammatory Reaction

“…A fundamental example is the use of islets from α1,3-galactosyltransferase total knockout (GTKO) (9), human CD46 transgenic pigs (12), and a recent study of porcine islets with multiple genetic modifications (27). Indeed, as clinical trials in islet xenotransplantation are contemplated (28–31) the use of transgenic porcine tissue is generally felt to be an essential component for meaningful engraftment with acceptable degrees of immunosuppression. However, preclinical work in the pig to primate model has made controlled studies of specific transgenes difficult, and conclusions based on numerous protocol variations have made it difficult to quantify the benefit of specific transgenic modifications (32).…”