Xenotransplantation of embryonic pig pancreas for treatment of diabetes mellitus in non-human primates

Marc R. Hammerman

George M. O’Brien Center, Department of Medicine, Washington University School of Medicine, St. Louis, USA.

DOI: 10.4236/jbise.2013.65A002                

Abstract

Transplantation therapy for diabetes in humans is limited by the low availability of human donor whole pancreas or islets. Outcomes are complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Pig insulin is biologically active in humans. In that regard the pig is an appropriate xenogeneic organ donor. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation [embryonic day 28 (E28)] engraft long-term in rhesus macaques. Endocrine cells originating from embryonic pig pancreas transplanted in host mesentery migrate to mesenteric lymph nodes, engraft, differentiate and improve glucose tolerance in rhesus macaques without the need for immune suppression. Transplantation of embryonic pig pancreas is a novel approach towards beta cell replacement therapy that could be applicable to humans.

Keywords

Beta Cell; Diabetes Mellitus; Non-Human Primates; Transplantation; Xenotransplantation

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	McCullough, K.P., Keith, D.S., Meyer, K.H., Stock, P.G., Brayman, K.L. and Leichtman, A.B. (2009) Kidney and pancreas transplantation in the United States 1998-2007. Access for patients with diabetes and end stage renal disease. American Journal of Transplantation, 9, 894-906. doi:10.1111/j.1600-6143.2009.02566.x
[2]	Bottino, R. and Trucco, M. (2005) Multifaceted therapeutic approaches for a multigenic disease. Diabetes, 54, S79-S86. doi:10.2337/diabetes.54.suppl_2.S79
[3]	Hering, B.J. and Walawalkar, N. (2009) Pig-to-nonhuman primate islet xenotransplantation. Transplant Immunology, 21, 81-86. doi:10.1016/j.trim.2009.05.001
[4]	Hammerman, M.R. (2012) Development of a novel xenotransplantation strategy for treatment of diabetes mellitus in rat hosts and translation to non-human primates. Organogenesis, 8, 41-48. doi:10.4161/org.20930
[5]	Rogers, S.A., Talcott, M. and Hammerman, M.R. (2003) Transplantation of pig metanephroi. ASAIO Journal, 49, 48-52. doi:10.1097/00002480-200301000-00008
[6]	Rogers, S.A., Liapis, H. and Hammerman, M.R. (2005) Normalization of glucose post-transplantation of pig pancreatic anlagen into non-immunosuppressed diabetic rats depends on obtaining anlagen prior to embryonic day 35. Transplant Immunology, 14, 67-75. doi:10.1016/j.trim.2005.02.004
[7]	Rogers, S.A., Chen, F., Talcott, M. and Hammerman, M.R. (2004) Islet cell engraftment and control of diabetes in rats following transplantation of pig pancreatic analgen. American Journal of Physiology, 286, E502-E509. doi:10.1152/ajpendo.00445.2003
[8]	Rogers, S.A. and Hammerman, M.R. (2008) Normalization of glucose post-transplantation into diabetic rats of pig pancreatic primordia preserved in vitro. Organogenesis, 4, 48-51. doi:10.4161/org.5747
[9]	Rogers, S.A. Mohanakumar, T, Liapis, H and Hammerman M.R. (2010) Engraftment of cells from porcine islets of Langerhans and normalization of glucose tolerance following transplantation of pig pancreatic primordia in non-immune suppressed diabetic rats. American Journal of Pathology, 177, 854-864. doi:10.2353/ajpath.2010.091193
[10]	Rogers, S.A., Chen, F., Talcott, M., Liapis, H. and Hammerman M.R. (2006) Glucose tolerance normalization following transplantation of pig pancreatic primordia into non-immunosuppressed diabetic ZDF rats. Transplant Immunology, 16, 176-184. doi:10.1016/j.trim.2006.08.007
[11]	Rogers, S.A., Chen, F., Talcott, M.R., Faulkner, C., Thomas, J.M., Thevis, M. and Hammerman M.R. (2007) Long-term engraftment following transplantation of pig pancreatic primordia into non-immunosuppressed diabetic rhesus macaques. Xenotransplantation, 14, 591-602. doi:10.1111/j.1399-3089.2007.00429.x
[12]	Rogers, S.A., Tripathi, P., Mohanakumar, T., Liapis, H., Chen F., Talcott, M.R, et al. (2011) Engraftment of cells from porcine islets of Langerhans following transplantation of pig pancreatic primordia in non-immune suppressed diabetic rhesus macaques. Organogenesis, 7, 154-162. doi:10.4161/org.7.3.16522
[13]	Hecht, G., Eventov-Friedman, S., Rosen, C., Shezen, E., Tchorsh, D., Aronovich, A., et al. (2009) Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model. Proceedings of the National Academy of Sciences of the United States of America, 106, 8659-8664. doi:10.1073/pnas.0812253106
[14]	Tchorsh-Yutsis, D., Hecht, G., Aronovich, A., Shezen, E., Klionsky, Y., Rosen, C., et al. (2009) Pig embryonic pancreatic tissue as a source for transplantation in diabetes: Transient treatment with anti-LFA1, anti-CD48 and FTY720 enables long term graft maintenance in mice with only mild ongoing immune suppression. Diabetes, 58, 1585-1594. doi:10.2337/db09-0112
[15]	Hoppo, T., Komori, J., Manohar, R., Stolz, D.B. and Lagasse, E. (2011) Rescue of lethal hepatic failure by hepatized lymph nodes in mice. Gastroenterology, 140, 565-666. doi:10.1053/j.gastro.2010.11.006
[16]	Graham, M.L. and Schuurman, H-J. (2013) The usefulness and limitations of the diabetic macaque model in evaluating long-term porcine islet xenograft survival. Xenotransplantation, 20, 5-17. doi:10.1111/xen.12012