Transplantation of xenogeneic islets: Are we there yet?

Current Diabetes Reports

Volumn 13, Issue 5, 2013, Pages 687-694

  O'Connell, Philip J ^a   Cowan, Peter J ^b,c   Hawthorne, Wayne J ^a   Yi, Shounan ^a   Lew, Andrew M ^d  

^a WESTMEAD HOSPITAL   (Australia)

^b ST VINCENT S HOSPITAL   (Australia)

^c UNIVERSITY OF MELBOURNE   (Australia)

^d WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH   (Australia)

Author keywords

Islet xenotransplantation; Transplantation; Type 1 diabetes; Xenogeneic islets

Indexed keywords

ACETYLSALICYLIC ACID; BASILIXIMAB; BELATACEPT; CD40 LIGAND MONOCLONAL ANTIBODY; COMPLEMENT COMPONENT C3A; COMPLEMENT COMPONENT C5A; EVEROLIMUS; FINGOLIMOD; GALACTOSYLGALACTOSE; LEFLUNOMIDE; MELAGATRAN; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; NICOTINAMIDE; ODULIMOMAB; RAPAMYCIN; TACROLIMUS; THYMOCYTE ANTIBODY;

ACUTE GRAFT REJECTION; ALLOTRANSPLANTATION; ARTICLE; CD4+ T LYMPHOCYTE; COMPLEMENT ACTIVATION; ENCAPSULATION; GENETIC MANIPULATION; GLYCEMIC CONTROL; GRAFT REJECTION; GRAFT SURVIVAL; HUMAN; IMMEDIATE BLOOD MEDIATED INFLAMMATORY REACTION; IMMUNOSUPPRESSIVE TREATMENT; INNATE IMMUNITY; INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS ISLET TRANSPLANTATION; PANCREAS ISLET XENOTRANSPLANTATION; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; XENOTRANSPLANTATION;

ANIMALS; GRAFT REJECTION; HETEROGRAFTS; HUMANS; IMMUNOSUPPRESSION; INFLAMMATION; ISLETS OF LANGERHANS TRANSPLANTATION; TRANSPLANTATION, HETEROLOGOUS;

EID: 84884594662     PISSN: 15344827     EISSN: 15390829     Source Type: Journal    
DOI: 10.1007/s11892-013-0413-9     Document Type: Article

References (69)

1. Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med. 2010;363:311-20.
2. Thompson DM, Meloche M, Ao Z, Paty B, Keown P, Shapiro RJ, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation. 2011;91:373-8.
3. Tiwari JL, Schneider B, Barton F, Anderson SA. Islet cell transplantation in type 1 diabetes: an analysis of efficacy outcomes and considerations for trial designs. Am J Transplant. 2012;12:1898-907.
4. Graham KL, Krishnamurthy B, Fynch S, Ayala-Perez R, Slattery RM, Santamaria P, et al. Intra-islet proliferation of cytotoxic T lymphocytes contributes to insulitis progression. Eur J Immunol. 2012;42:1717-22.
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.
6. Moberg L, Johansson H, Lukinius A, Berne C, Foss A, Kallen R, et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet. 2002;360:2039-45.
7. Bennet W, Sundberg B, Groth CG, et al. Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes. 1999;48:1907-14.
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.
9. Cowan PJ, d'Apice AJ. The coagulation barrier in xenotransplantation: incompatibilities and strategies to overcome them. Curr Opin Organ Transplant. 2008;13:178-83.
10. Hamad OA, Back J, Nilsson PH, Nilsson B, Ekdahl KN. Platelets, complement, and contact activation: partners in inflammation and thrombosis. Adv Exp Med Biol. 2012;946:185-205.
11. Owens III AP, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res. 2011;108:1284-97.
12. Rayat GR, Rajotte RV, Hering BJ, Binette TM, Korbutt GS. In vitro and in vivo expression of Galalpha-(1,3)Gal on porcine islet cells is age dependent. J Endocrinol. 2003;177:127-35.
13. van der Windt DJ, Bottino R, Casu A, Campanile N, Cooper DK. Rapid loss of intraportally transplanted islets: an overview of pathophysiology and preventive strategies. Xenotransplantation. 2007;14:288-97.
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.
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.
16. Lundgren T, Bennet W, Tibell A, Soderlund J, Sundberg B, Song Z, et al. Soluble complement receptor 1 (TP10) preserves adult porcine islet morphology after intraportal transplantation into cynomolgus monkeys. Transplant Proc. 2001;33:725.
17. Ryan EA, Lakey JR, Rajotte RV, et al. Clincal outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes. 2001;50:710-9.
18. Villiger P, Ryan EA, Owen R, O'Kelly K, Oberholzer J, Al Saif F, et al. Prevention of bleeding after islet transplantation: lessons learned from a multivariate analysis of 132 cases at a single institution. Am J Transplant. 2005;5:2992-8.
19. Moberg L, Olsson A, Berne C, Felldin M, Foss A, Kallen R, et al. Nicotinamide inhibits tissue factor expression in isolated human pancreatic islets: implications for clinical islet transplantation. Transplantation. 2003;76:1285-8.
20. Cabric S, Sanchez J, Johansson U, Larsson R, Nilsson B, Korsgren O, et al. Anchoring of vascular endothelial growth factor to surface-immobilized heparin on pancreatic islets: implications for stimulating islet angiogenesis. Tissue Eng. 2010;16:961-70.
21. Gill RG, Wolf L, Daniel D, Coulombe M. CD4+ T-cells are both necessary and sufficient for islet xenograft rejection. Transplant Proc. 1994;26:1203.
22. Loudovaris T, Mandel TE, Charlton B. CD4+ T-cell mediated destruction of xenografts within cell-impermeable membranes in the absence of CD8+ T-cells and B cells. Transplantation. 1996;61:1678-84.
23. Xu BY, Yang H, Serreze DV, MacIntosh R, Yu W, Wright Jr JR. Rapid destruction of encapsulated islet xenografts by NOD mice is CD4-dependent and facilitated by B-cells: innate immunity and autoimmunity do not play significant roles. Transplantation. 2005;80:402-9.
24. Simeonovic CJ, Ceredig R, Wilson JD. Effect of GK1.5 monoclonal antibody dosage on survival of pig proislet xenografts in CD4+ T-cell-depleted mice. Transplantation. 1990;49:849-56.
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.
26. Yi S, Feng X, Hawthorne WJ, Patel AT, Walters SN, O'Connell PJ. CD4+ T-cells initiate pancreatic islet xenograft rejection via an interferon-gamma-dependent recruitment of macrophages and natural killer cells. Transplantation. 2002;73:437-46.
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.
28. Friedman T, Smith RN, Colvin RB, Iacomini J. A critical role for human CD4+ T-cells in rejection of porcine islet cell xenografts. Diabetes. 1999;48:2340-8.
29. Tonomura N, Shimizu A, Wang S, Yamada K, Tchipashvili V, Weir GC, et al. Pig islet xenograft rejection in a mouse model with an established human immune system. Xenotransplantation. 2008;15:129-35.
30. Hering BJ, Wijkstrom M, Graham ML, Hardstedt M, Aasheim TC, Jie T, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med. 2006;12:301-3.
31. Cardona K, Korbutt GS, Milas Z, Lyon J, Cano J, Jiang W, et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med. 2006;12:304-6.
32. Yamada K, Sachs DH, DerSimonian H. Human anti-porcine xenogeneic T-cell response. Evidence for allelic specificity of mixed leukocyte reaction and for both direct and indirect pathways of recognition. J Immunol. 1995;155:5249-56.
33. Murray AG, Khodadoust MM, Pober JS, Bothwell AL. Porcine aortic endothelial cells activate human T-cells: direct presentation of MHC antigens and costimulation by ligands for human CD2 and CD28. Immunity. 1994;1:57-63.
34. Koulmanda M, Laufer TM, Auchincloss Jr H, Smith RN. Prolonged survival of fetal pig islet xenografts in mice lacking the capacity for an indirect response. Xenotransplantation. 2004;11:525-30.
35. Olack BJ, Jaramillo A, Benshoff ND, Kaleem Z, Swanson CJ, Lowell JA, et al. Rejection of porcine islet xenografts mediated by CD4+ T-cells activated through the indirect antigen recognition pathway. Xenotransplantation. 2002;9:393-401.
36. Auchincloss Jr H, Sachs DH. Xenogeneic transplantation. Annu Rev Immunol. 1998;16:433-70.
37. Yang YG, Sykes M. Xenotransplantation: current status and a perspective on the future. Nat Rev. 2007;7:519-31.
38. Schmidt P, Krook H, Maeda A, Korsgren O, Benda B. A new murine model of islet xenograft rejection: graft destruction is dependent on a major histocompatibility-specific interaction between T-cells and macrophages. Diabetes. 2003;52:1111-8.
39. Wu GS, Korsgren O, Zhang JG, Song ZS, Van Rooijen N, Tibell A. Role of macrophages and natural killer cells in the rejection of pig islet xenografts in mice. Transplant Proc. 2000;32:1069.
40. Andres A, Toso C, Morel P, Bosco D, Bucher P, Oberholzer J, et al. Macrophage depletion prolongs discordant but not concordant islet xenograft survival. Transplantation. 2005;79:543-9.
41. Yi S, Hawthorne WJ, Lehnert AM, Ha H, Wong JK, van Rooijen N, et al. T-cell-activated macrophages are capable of both recognition and rejection of pancreatic islet xenografts. J Immunol. 2003;170:2750-8.
42. Chang TM. Therapeutic applications of polymeric artificial cells. Nat Rev Drug Discov. 2005;4:221-35.
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.
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.
45. Nilsson B, Ekdahl KN, Korsgren O. Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment. Curr Opin Organ Transplant. 2011;16:620-6.
46. Cowan PJ, d'Apice AJ. Complement activation and coagulation in xenotransplantation. Immunol Cell Biol. 2009;87:203-8.
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.
48. van der Windt DJ, Bottino R, Casu A, Campanile N, Smetanka C, He J, et al. Long-term controlled normoglycemia in diabetic nonhuman primates after transplantation with hCD46 transgenic porcine islets. Am J Transplant. 2009;9:2716-26.
49. Wheeler DG, Joseph ME, Mahamud SD, Aurand WL, Mohler PJ, Pompili VJ, et al. Transgenic swine: expression of human CD39 protects against myocardial injury. J Mol Cell Cardiol. 2012;52:958-61.
50. Yazaki S, Iwamoto M, Onishi A, Miwa Y, Hashimoto M, Oishi T, et al. Production of cloned pigs expressing human thrombomodulin in endothelial cells. Xenotransplantation. 2012;19:82-91.
51. Dwyer KM, Mysore TB, Crikis S, Robson SC, Nandurkar H, Cowan PJ, et al. The transgenic expression of human CD39 on murine islets inhibits clotting of human blood. Transplantation. 2006;82:428-32 [Epub 2006/08/15].
52. Schneider MK, Seebach JD. Current cellular innate immune hurdles in pig-to-primate xenotransplantation. Curr Opin Organ Transplant. 2008;13:171-7.
53. Wang H, Yang YG. Innate cellular immunity and xenotransplantation. Curr Opin Organ Transplant. 2012;17:162-7.
54. Weiss EH, Lilienfeld BG, Muller S, Muller E, Herbach N, Kessler B, et al. HLA-E/human beta2-microglobulin transgenic pigs: protection against xenogeneic human anti-pig natural killer cell cytotoxicity. Transplantation. 2009;87:35-43.
55. Ide K, Wang H, Tahara H, Liu J, Wang X, Asahara T, et al. Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages. Proc Natl Acad Sci U S A. 2007;104:5062-6.
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.
57. Brady JL, Mannering SI, Kireta S, Coates PT, Proietto AI, Cowan PJ, et al. Monoclonal antibodies generated by DNA immunization recognize CD2 from a broad range of primates. Immunol Cell Biol. 2009;87:413-8.
58. Lowe M, Badell IR, Thompson P, Martin B, Leopardi F, Strobert E, et al. A novel monoclonal antibody to CD40 prolongs islet allograft survival. Am J Transplant. 2012;12:2079-87.
59. Lowe MC, Badell IR, Turner AP, Thompson PW, Leopardi FV, Strobert EA, et al. Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy. Am J Transplant. 2013;13:312-9.
60. Carrington EM, Vikstrom IB, Light A, Sutherland RM, Londrigan SL, Mason KD, et al. BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs. Proc Natl Acad Sci U S A. 2010;107:10967-71.
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.
62. Geissler EK. Fighting malignancy in organ transplant recipients. Transplant Proc. 2009;41(6 Suppl):S9-12.
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.
64. Londrigan SL, Sutherland RM, Brady JL, Carrington EM, Cowan PJ, d'Apice AJ, et al. In situ protection against islet allograft rejection by CTLA4Ig transduction. Transplantation. 2010;90:951-7.
65. Ramji QA, Bayrack K, Arefanian H, Marcet-Palacios M, Bleackley RC, Rajotte RV, et al. Protection of porcine islet xenografts in mice using sertoli cells and monoclonal antibodies. Transplantation. 2011;92:1309-15.
66. Reading JL, Sabbah S, Busch S, Tree TI. Mesenchymal stromal cells as a means of controlling pathological T-cell responses in allogeneic islet transplantation. Curr Opin Organ Transplant. 2013;18:59-64.
67. Sun G, Shan J, Li Y, Zhou Y, Guo Y, Wu W, et al. Adoptive infusion of tolerogenic dendritic cells prolongs the survival of pancreatic islet allografts: a systematic review of 13 mouse and rat studies. PLoS One. 2012;7:e52096.
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.
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.