Rapid failure of pig islet transplantation in non human primates

Abstract

We have previously demonstrated that adult pig islets of Langerhans are not destroyed in vitro by primate sera. Whether these islets can function when placed into the liver of non-human primates is not known. We now report on the outcome of pig islet xenotransplantation into five non diabetic primates (four baboons and one macacus fascicularis) receiving intraportally purified adult pig islets. The average number of islet-equivalent per graft was 110,000 (60-180,000). All animals received associations of ATG, cyclosporine or LF 195 (a deoxyspergualin analog), mycophenolate mofetil and corticosteroids. A specific porcine C-peptide (C-pep) RIA test was used to monitor insulin secretion. Two hours after grafting, porcine C-peptide was positive (from 0.37 to 4.25 ng/ml) in all monkeys except one. Primate C-pep was normal in all cases. Only two monkeys had detectable levels of porcine C-pep on day 1 or 2 with undetectable levels thereafter, even after glucagon challenge between days 6 and 10. Several normal islets with moderate inflammatory infiltration were observed in one animal liver on day 2 (the time of necropsy) as well as islets with IgM and complement deposition. Among animals sacrificed on days 14, 16 and 38, some residual islet cells could be identified only in livers collected on day 14. Partial glycaemic control was achieved in some rats receiving islets from the same preparations. In conclusion, adult pig islets are not able to maintain insulin secretion for more than 24 h when injected intraportally into non diabetic immunosuppressed monkeys. suggesting immediate islet xenograft destruction.

Use of the Gottingen Minipig as a Model of Diabetes, with Special Focus on Type 1 Diabetes Research

“…In nonhuman primates, the function of adult pig islets in both nondiabetic and diabetic immunosuppressed animals has been shown to be very short lasting, indicating almost immediate graft destruction in this species Cantarovich et al 2002). In contrast, a regimen including splenectomy and irradiation prolonged graft survival to more than 2 wk, although it failed to prevent rejection thereafter .…”

Islet xenotransplantation: progress towards a clinical therapy

“…Therefore, it is important to note that when adult pig islets have been transplanted intra-portally into baboons, the xenografts were destroyed within a few days despite receiving strong immunosuppression. Cantarovich et al [14] infused adult pig islets (11 000 IEQ/kg; range 6000-50 000) into the portal circulation of five non-diabetic primates (four baboons and one macaque). All grafts failed within 3 days despite immunosuppression with cyclosporin, mycophenolate mofetil, ATG and high-dose methylprednisolone.…”

“…Two studies have shown rapid destruction of adult pig islets transplanted intraportally into baboons, with few or no viable islets remaining by day 2 and evidence of thrombosis and deposition of antibody and complement [13,14]. A pig-to-macaque model showed destruction of most islets within 3 days, with early deposition of humoral components, although in this case rejection was predominantly mediated by an acute cellular mechanism with little evidence of intraportal thrombosis [2 ].…”

Pig islets for clinical islet xenotransplantation

“…Diffuse, presumably nonspecific IgG deposits were noted within islet-associated platelet accumulations 12 h after transplantation. Considerable IgM and moderate-tostrong C3, C5, and C9 depositions were present on islet surfaces 2-3 days after xenograft [54][55][56]. Antigalactosyl (anti-Gal) and non-Gal [57,58] IgM antibodies bind to islet surfaces soon after transplantation and activate the classic complement pathway and neutrophil infiltration.…”