Transplantation of Xenogeneic Islets: Are We There Yet?
- 454 Downloads
Beta cell replacement therapy has been proposed as a novel therapy for the treatment of type 1 diabetes. The proof of concept has been demonstrated with successful islet allotransplantation. Islet xenotransplantation has been proposed as an alternative, more reliable, and infinite source of beta cells. The advantages of islet xenotransplantation are the ability to transplant a well differentiated cell that is responsive to glucose and the potential for genetic modification which focuses the treatment on the donor rather than the recipient. The major hurdle remains overcoming the severe cellular rejection that affects xenografts. This review will focus on the major advances that have occurred with genetic modification and the successful therapeutic strategies that have been demonstrated in nonhuman primates. Novel approaches to overcome cell-mediated rejection including biological agents that target selectively costimulation molecules, the development of local immunosuppression through genetic manipulation, and encapsulation will be discussed. Overall, there has been considerable progress in all these areas, which eventually should lead to clinical trials.
KeywordsTransplantation Xenogeneic islets Type 1 diabetes Islet xenotransplantation
Compliance with Ethics Guidelines
Conflict of Interest
Philip J. O’Connell declares that he has no conflict of interest.
Peter J. Cowan has received grant support from National Health & Medical Research Council of Australia; Juvenile Diabetes Research Foundation (Program Grant #447718: Which transgenic pig will be used for islet transplantation in humans?).
Wayne J. Hawthorne declares that he has no conflict of interest.
Shounan Yi declares that he has no conflict of interest.
Andrew M. Lew has received grant support from National Health & Medical Research Council and Juvenile Diabetes Research Foundation for diabetes research. He has also received support in kind such as writing, provision of medicines or equipment, or administrative support from Victorian state government for support for infrastructure costs.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 5.Ozmen L, Ekdahl KN, Elgue G, Larsson R, Korsgren O, Nilsson B. Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation. Diabetes. 2002;51:1779–84.PubMedCrossRefGoogle Scholar
- 8.• Ji M, Yi S, Smith-Hurst H, Phillips P, Wu J, Hawthorne W, et al. The importance of tissue factor expression by porcine NICC in triggering IBMIR in the xenograft setting. Transplantation. 2011;91:841–6. This paper shows that reduction in tissue factor expression will lead to a reduction in the severity of IBMIR.PubMedCrossRefGoogle Scholar
- 14.Contreras J, Eckstein C, Smyth CA, Bilbao G, Vilatoba M, Ringland SE, et al. Activated protein C preserves functional islet mass after intraportal transplantation: a novel link between endothelial cell activation, thrombosis, inflammation, and islet cell death. Diabetes. 2004;53:2804–14.PubMedCrossRefGoogle Scholar
- 15.Akima S, Hawthorne WJ, Koutts J, et al, editor. Differences in the efficacy of recombinant human activated protein C against allogeneic and xenogeneic IBMIR. 24th annual scientific meeting of the TSANZ. Austalian Academy of Science, Canberra; 2006.Google Scholar
- 25.Koulmanda M, McKenzie I, Sandrin M, Mandel T. Fetal pig xenografts in NOD/Lt mice: lack of expression of Gal(alpha 1–3)Gal on endocrine cells and the effect of peritransplant anti-CD4 monoclonal antibody and graft immunomodification on graft survival. Transplant Proc. 1995;27:3570.PubMedGoogle Scholar
- 27.• Yi S, Ji M, Wu J, Ma X, Phillips P, Hawthorne WJ, et al. Adoptive transfer with in vitro expanded human regulatory T-cells protects against porcine islet xenograft rejection via interleukin-10 in humanized mice. Diabetes. 2012;61:1180–91. This manuscript shows that the human T-cell response to islet xenografts can be modified and suppressed by expanded naïve Treg cells that secrete IL-10. Google Scholar
- 37.Yang YG, Sykes M. Xenotransplantation: current status and a perspective on the future. Nat Rev. 2007;7:519–31.Google Scholar
- 43.• Carlson DF, Tan W, Lillico SG, Stverakova D, Proudfoot C, Christian M, et al. Efficient TALEN-mediated gene knockout in livestock. Proc Natl Acad Sci U S A. 2012;109:17382–7. This paper highlights some of the efficiencies in livestock cloning and gene modification that may benefit islet xenotransplantation. It shows that TALEN represents a highly facile platform for the modification of livestock genomes for both biomedical and agricultural applications.PubMedCrossRefGoogle Scholar
- 44.• Fisicaro N, Londrigan SL, Brady JL, Salvaris E, Nottle MB, O’Connell PJ, et al. Versatile co-expression of graft-protective proteins using 2A-linked cassettes. Xenotransplantation. 2011;18:121–30. Describes how the 2A ribosome skip isgnal can be used to express several transgenes with different processing and localizing mechanisms in a single transgenic construct.PubMedCrossRefGoogle Scholar
- 47.•• Thompson P, Badell IR, Lowe M, Cano J, Song M, Leopardi F, et al. Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function. Am J Transplant. 2011;11:2593–602. This paper shows the benefits of using genetically modified pigs to enhance survival. It shows that removal of the αGal antigen enhances islet xenograft survival in nonhuman primates.PubMedCrossRefGoogle Scholar
- 56.•• Klymiuk N, van Buerck L, Bahr A, Offers M, Kessler B, Wuensch A, et al. Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. Diabetes. 2012;61:1527–32. This important paper describes the generation of transgenic pigs expressing LEA29Y, a high-affinity variant of the T-cell costimulation inhibitor CTLA-4Ig, under the control of the porcine insulin gene promoter. NICC from these pigs were able to ovoid rejection by human T-cells in a humanized mouse model of islet xenotransplantation and shows the utility of local immunosuppression for protecting the graft.PubMedCrossRefGoogle Scholar
- 61.Khattar M, Deng R, Kahan BD, Schroder PM, Phan T, Rutzky LP, et al. Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T-cells induces permanent acceptance of pancreatic islet allografts. Transplantation. 2013;95:919–27.Google Scholar
- 63.• Brady JL, Sutherland RM, Hancock M, Kitsoulis S, Lahoud MH, Phillips PM, et al. Anti-CD2 producing pig xenografts effect localized depletion of human T-cells in a huSCID model. Xenotransplantation. 2013;20:100–9. This paper demonstrates the potential benefits of local immunosuppression and its ability to avoid systemic immunosuppression. Local production of a single Ab against T-cells reduced graft infiltration at the xenograft site and may reduce the need for conventional, systemic immunosuppression. Google Scholar
- 68.•• Dufrane D, Goebbels RM, Gianello P. Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression. Transplantation. 2010;90:1054–62. A very important paper showing that Pig islets encapsulated in a subcutaneous alginate macrodevice can control diabetes up to 6 months without immunosuppression in nonhuman primates.PubMedCrossRefGoogle Scholar
- 69.•• Thompson P, Cardona K, Russell M, Badell IR, Shaffer V, Korbutt G, et al. CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Am J Transplant. 2011;11:947–57. Most studies that have shown long term islet xenograft survival in primates have relied on administration of anti-CD154 mAb to prevent rejection. This agent cannot be used clinically. This study showed that anti-CD154 mAb could be substituted with an anti-CD40 mAb and enable functioning islet xenograft survival. Hence, it may form the basis of an immunosuppressive protocol that could be taken to the clinic.PubMedCrossRefGoogle Scholar