Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model.
Xenotransplantation of pig tissues has great potential to overcome the shortage of organ donors. One approach to address the vigorous immune rejection associated with xenotransplants is the use of embryonic precursor tissue, which induces and utilizes host vasculature upon its growth and development. Recently, we showed in mice that embryonic pig pancreatic tissue from embryonic day 42 (E42) exhibits optimal properties as a beta cell replacement therapy. We now demonstrate the proof of concept in 2 diabetic Cynomolgus monkeys, followed for 393 and 280 days, respectively. A marked reduction of exogenous insulin requirement was noted by the fourth month after transplantation, reaching complete independence from exogenous insulin during the fifth month after transplantation, with full physiological control of blood glucose levels. The porcine origin of insulin was documented by a radioimmunoassay specific for porcine C-peptide. Furthermore, the growing tissue was found to be predominantly vascularized with host blood vessels, thereby evading hyperacute or acute rejection, which could potentially be mediated by preexisting anti-pig antibodies. Durable graft protection was achieved, and most of the late complications could be attributed to the immunosuppressive protocol. While fine tuning of immune suppression, tissue dose, and implantation techniques are still required, our results demonstrate that porcine E-42 embryonic pancreatic tissue can normalize blood glucose levels in primates. Its long-term proliferative capacity, its revascularization by host endothelium, and its reduced immunogenicity, strongly suggest that this approach could offer an attractive replacement therapy for diabetes.
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Gil
G
Hecht
Smadar
S
Eventov-Friedman
Chava
C
Rosen
Elias
E
Shezen
Dalit
D
Tchorsh
Anna
A
Aronovich
Enrique
E
Freud
Hana
H
Golan
Ronit
R
El-Hasid
Helena
H
Katchman
Bernhard J
BJ
Hering
Amnon
A
Zung
Zipi
Z
Kra-Oz
Pninit
P
Shaked-Mishan
Alex
A
Yusim
Alex
A
Shtabsky
Pavel
P
Idelevitch
Ana
A
Tobar
Alon
A
Harmelin
Esther
E
Bachar-Lustig
Yair
Y
Reisner
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000601:surgery*; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D010179:Pancreas / Q000098:blood supply / Q000196:embryology* / Q000276:immunology / Q000601:surgery*; D016035:Pancreas Transplantation; D013311:Streptozocin / Q000494:pharmacology; D013552:Swine / Q000196:embryology* / Q000601:surgery*; D014183:Transplantation, Heterologous / Q000276:immunology
D013311:Streptozocin