Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study

Abstract

Objective: Porcine islets of Langerhans for xenotransplantation into humans have been proposed as a solution to the shortage of human donors. Rejection is one of the main constraints. This study presents the results of a clinical trial using a novel method for transplanting and immunoprotecting porcine islets in type 1 diabetic patients. Design: A 4-year follow up of a clinical trial involving 12 patients, with no immunosuppressive drugs at any point. Eleven age matched untransplanted diabetics served as controls. Methods: We have developed a procedure for protecting neonatal porcine islets by combining them with Sertoli cells and placing them in a novel subcutaneous autologous collagen-covered device. Results: In the patients in the treatment group, no complications arose and no porcine endogenous retrovirus infection was detected. Half of the patients showed a significant reduction in insulin requirements compared with both their pre transplant levels and controls, and this reduction was maintained for up to 4 years. Two patients became insulin-independent for several months. Porcine insulin was detected in three patients' sera following glucose stimulation up to 4 years post transplant. Three years post transplant, one of four devices was removed from four patients, and the presence of insulin-positive cells in the transplant was demonstrated by immunohistology in all 4 patients. Conclusions: Long-term cell survival with concurrent positive effects on metabolic control are possible by this technique.

Cell Replacement Therapy: The Rationale for Encapsulated Porcine Islet Transplantation

“…However, this approach will not eliminate porcine endogenous retrovirus sequences (PERVs), which are present in the germline of all pigs (including common New Zealand pig breeds) but cause no known infection in the species. The possible transmission of these retroviruses to humans, and their as yet unknown consequences in recipients, have given rise to some concerns over the safety of xenotransplantation, particularly in view of reports that PERVs from certain pig strains can infect human cells in vitro (Patience et al 1997;Martin et al 1998a) and that immune-incompetent SCID (severe combined immunodeficiency) mice may develop either microchimerism or infection in vivo (van der Laan et al 2000). The in vitro findings have, however, been shown to be strain-specific (Patience 2001;Clemenceau et al 2001;Oldmixon et al 2002) and cells from animals studied by LCT have not shown retrovirus infectivity.…”

“…Islets in both perfusion devices and diffusion chambers are usually immobilised with alginate or agar to prevent settling and to provide uniform distribution of nutrients and dissolved oxygen and carbob-dioxide (Maki et al 1995).  Co-transplantation with 'nursery' cells such as testicular Sertoli cells which have been claimed to protect against immune-mediated rejection via the production of the immunomodulator TGF-beta1 (transforming growth factor-beta 1) (Suarez-Pinzon et al 2000;Valdes-Gonzalez, 2005).…”

Investigating design principles of micropatterned encapsulation systems containing high-density microtissue arrays

“…For example, TheraCyte™ devices encapsulate cells/tissues in sealed polytetrafluoroethylene (PTFE)-based membranes [30,31]; islets were also encapsulated in stainless steel mesh tubes with an interior PTFE rod [32]. In these devices, the spatial distribution of microtissues is random, uncontrollable and therefore unable to maintain the microtissues separated when closely packed together.…”

Glucocorticoid treatment independently affects expansion and transdifferentiation of porcine neonatal pancreas cell clusters

“…However, the shortage of human sources of islets as well as the high frequency of immune rejection of transplanted tissue remain obstacles that need to be overcome. Previously, we reported that porcine neonatal pancreatic cell clusters (NPCCs) contain many duct-like precursor cells and have considerable capacity for growth and transdifferentiation into β-cells compared to cells in the adult pancreas, making porcine NPCCs a useful alternative source of islets for transplantation (7)(8)(9)(10). Clinical application of xenograft stem cells, such as transplantation of porcine NPCCs, still requires that the major obstacle of xenogenic immune rejection be overcome.…”