Journal List > J Korean Soc Transplant > v.23(3) > 1034292

J Korean Soc Transplant. 2009 Dec;23(3):214-226. Korean.
Published online December 31, 2009.
Copyright © 2009 The Korean Society for Transplantation
Current Strategies for Successful Islet Xenotransplantation
Hwajung Kim, Ph.D.,1 Jaeseog Yang, M.D.,2 and Curie Ahn, M.D.3
1Transplantation Research Institute, Seoul National University Medical Research Center, Seoul, Korea.
2Transplantation Center Seoul National, University Hospital, Transplantation Research Institute, Seoul National University Medical Research Center, Seoul, Korea.
3Division of Nephrology, Transplantation Research Institute, Seoul National University Medical Research Center, Seoul, Korea.

Corresponding author (Email: )
Received December 28, 2009; Accepted December 28, 2009.


Diabetes mellitus is increasing all over the world and is a serious health problem. Pancreatic islet transplantation is promising treatment for diabetes mellitus, but an imbalance between deceased pancreas donors and recipients limited the widespread clinical application. Therefore, pig islets could be used as an alternative islet source in transplantation. However, a big hurdle to clinical application of islet xenotransplantation is the instant blood mediated inflammatory reaction (IBMIR), which is characterized by activation of the coagulation cascade, platelets and complement systems. Innate immune cells infiltrate the islets in the process of IBMIR and thereby accelerate the early graft loss. Characteristics of IBMIR in islet xenotransplantion are very different from the rejection in solid organ xenotransplantation. Therefore, we focus on the molecules for surmounting IBMIR in order to accomplish successful islet xenotransplantation. To prevent the IBMIR in islet xenotransplantation, development of genetic modified pigs containing anti-coagulant, anti-thrombosis and complement regulatory genes, or capsulation of islet with biomaterials for blocking immune response around islet surface can be tried. Gα-Gal knockout pigs and the diverse transgenic pigs for complement regulatory protein or anti-coagulant genes have been developed for xenotransplantation. This review summarized on characteristics of rejection in islet xenotransplantation and discusses the strategies for overcoming the rejection.

Keywords: Islet xenotransplantation; Instant blood mediated inflammatory reaction (IBMIR); Genetically modified pig; Diabetes mellitus


Fig. 1
Treatment of diabetes mellitus-strength & weakness.
Click for larger image

Fig. 2
Three stages of graft rejection in xenotransplantation. (A) Hyperacute rejection: Hyperacute rejection of pig organs in humans is induced by binding of preformed human 'natural' antibody, which is generally directed against Gala1-3Gal that exists on the surface of pig cells. Complement is activated by antibody binding, and triggers lysis of endothelial cells. (B) Acute vascular rejection: Acute vascular rejection is induced by interactions between the graft endothelial cells and host antibodies, macrophages, and platelets. The response is characterized by an inflammatory infiltrate of mostly macrophages and natural killer cells (with small numbers of T cells), intravascular thrombosis, and fibrinoid necrosis of vessel walls. (C) Acute cellular rejection: Cellular rejection is caused by cellular immunity i) Natural killer cells, which accumulate in and damage the xenograft, and ii) T-lymphocytes, which are activated by MHC molecules through both direct and indirect xenorecognition.

Abbreviations: MHC, major histocompatibility complex.

Click for larger image

Fig. 3
Putative model for the IBMIR. (A) In contact with blood, IgG and IgM antibodies bind to the islet surface and activate complement which leads to deposition of C3b/iC3b to the surface. (B) Tissue factor (TF) activates the coagulation system via the extrinsic pathway. As a consequence of extrinsic pathway activation, prothrombin is cleaved into thrombin. Thrombin subsequently generates fibrin and activates platelets. (C) Platelet activation increases the affinity of the integrins GPIIb-IIIa and a2b1 for fibrin and collagen, respectively. Activated platelets bind to fibrin and collagen on the islet surface. (D) Amplified by platelets, thrombin generates more fibrin creating a capsule containing platelets, PMNs, and monocytes surrounding the islets. Chemotactic factors (e.g., C5a and IL-8) that were released as a consequence of IBMIR or released directly from the islets (e.g., MCP-1, IL-8 etc.), exert their action on PMNs and monocytes that infiltrate the islets in large numbers after 30 min.

Abbreviations: IBMIR, instant blood mediated inflammatory reaction; IL-8, Interleukin-8; PMNs, polymorphonuclear leukocytes; MCP-1, monocyte chemoattractant protein-1.

Source: Nilson B. The instant blood-mediated inflammatory reaction in xenogeneic islet transplantation. Xenotransplantation 2008;15:96-8. p.97.

Click for larger image

Fig. 4
Schematic representation of the coagulation pathways. 'a' present the activated clotting factors. Briefly, coagulation is initiated when islet-expressed tissue factor (TF) is exposed to the blood in IBMIR. TF then complexes with VIIa and enhances its activity. This sequence of coagulation activation is known as the extrinsic pathway. The complex of VIIa/TF activates factors IXa and Xa, which mediate the conversion of prothrombin into the active thrombin. Nevertheless, the small quantity of thrombin formed is sufficient to activate XIa, which reinforces thrombin generation by activating the intrinsic pathway. Furthermore, the intrinsic pathway can be activated by collagen residues or other negatively charged molecules on the islet surface. Thrombin, a potent platelet activator, cleaves fibrinogen into fibrin monomers, and activates the coagulation factor that cross-links fibrin monomers into an insoluble thrombus (XIIIa, not shown). Coagulation systems can be modulated by anti-coagulant molecules as TBM (thrombomodulin), TFPI (tissue factor pathway inhibitor), AT (antithrombin) and CD39 (ectoATPase).

Source: 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. p.289.

Click for larger image

Fig. 5
Schematic representation of the complement cascades. The membrane attack complex is initiated when C5 convertase cleaves C5 into C5a and C5b. After C6, binds to C5b, the C5bC6 complex is bound by C7. This junction alters the configuration of the protein molecules exposing a hydrophobic site on C7 that allows the C7 to insert into the phospholipid bilayer of the pathogen. Similar hydrophobic sites on C8 and C9 molecules are exposed when they bind to the complex, so that they can also insert into the bilayer. The ring structure formed by C9 is a pore in the membrane that allows free diffusion of molecules in and out of the cell. If enough pores form, the cell is no longer able to survive. There is a membrane bound complement regulator such as DAF (CD55), CD59, and MCP (CD46). CD46 is an inhibitory complement receptor and decay accelerating factor (CD55) is a 70 kDa membrane protein that regulates the complement system on the cell surface. CD59 inhibits the complement membrane attack complex by binding C5b678 and preventing C9 from binding and polymerizing.

Abbreviations: MBL, Mannose binding lectin; MASP, MBL-associated serine protease; DAF, decay accelerating factor; MCP, membrane cofactor pretein.

Source: 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. p.290.

Click for larger image

Fig. 6
Transgenic pigs production for overcoming graft rejection in xeotransplantation.
Click for larger image

1. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782–787.
2. Korea National Health and Nutrition Examination Survey. Seoul: The Korea Centers for Disease Control and Prevention; 2009. Korea National Health and Nutrition Examination Survey 2005 [internet].
Available from:
3. Scharp DW, Lacy PE, Santiago JV, McCullough CS, Weide LG, Falqui L, et al. Insulin independence after islet transplantation into type I diabetic patient. Diabetes 1990;39:515–518.
4. Park JB, Kim SJ. Clinical islet transplantation: where do we stand on? J Korean Soc Transplant 2007;21:196–202.
5. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230–238.
6. Rood PP, Buhler LH, Bottino R, Trucco M, Cooper DK. Pig-to-nonhuman primate islet xenotransplantation: a review of current problems. Cell Transplant 2006;15:89–104.
7. Reemtsma K, McCracken BH, Schlegel JU, Pearl MA, Pearce CW, Dewitt CW, et al. Renal heterotransplantation in man. Ann Surg 1964;160:384–410.
8. Bailey LL, Nehlsen-Cannarella SL, Concepcion W, Jolley WB. Baboon-to-human cardiac xenotransplantation in a neonate. JAMA 1985;254:3321–3329.
9. Pruitt SK, Kirk AD, Bollinger RR, Marsh HC Jr, Collins BH, Levin JL, et al. The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts. Transplantation 1994;57:363–370.
10. Tseng YL, Kuwaki K, Dor FJ, Shimizu A, Houser S, Hisashi Y, et al. alpha1,3-Galactosyltransferase gene-knockout pig heart transplantation in baboons with survival approaching 6 months. Transplantation 2005;80:1493–1500.
11. Rayat GR, Gill RG. Indefinite survival of neonatal porcine islet xenografts by simultaneous targeting of LFA-1 and CD154 or CD45RB. Diabetes 2005;54:443–451.
12. Choi I, Kim SD, Cho B, Kim D, Park D, Koh HS, et al. Xenogeneic interaction between human CD40L and porcine CD40 activates porcine endothelial cells through NF-kappaB signaling. Mol Immunol 2008;45:575–580.
13. Ahn C, et al. Fgl2 induction in porcine endothelial cells through xenogeneic CD40-CD40L interaction.
(in press).
14. Lee EM, Park JO, Kim D, Kim JY, Oh KH, Park CG, et al. Early up-regulation of CXC-chemokine expression is associated with strong cellular immune responses to murine skin xenografts. Xenotransplantation 2006;13:328–336.
15. Kim JY, Kim D, Lee EM, Choi I, Park CG, Kim KS, et al. Inducible nitric oxide synthase inhibitors prolonged the survival of skin xenografts through selective down-regulation of pro-inflammatory cytokine and CC-chemokine expressions. Transpl Immunol 2003;12:63–72.
16. Yang J, Cho B, Choi I, Kim DH, Kim SD, Koh HS, et al. Molecular characterization of miniature porcine RANTES and its chemotactic effect on human mononuclear cells. Transplantation 2006;82:1229–1233.
17. Yang J, Choi I, Kim SD, Kim ES, Cho B, Kim JY, et al. Molecular characterization of cDNA encoding porcine IP-10 and induction of porcine endothelial IP-10 in response to human TNF-alpha. Vet Immunol Immunopathol 2007;117:124–128.
18. Choi I, Cho B, Kim SD, Park D, Kim JY, Park CG, et al. Molecular cloning, expression and functional characterization of miniature swine CD86. Mol Immunol 2006;43:480–486.
19. Nilsson B. The instant blood-mediated inflammatory reaction in xenogeneic islet transplantation. Xenotransplantation 2008;15:96–98.
20. Bennet W, Groth CG, Larsson R, Nilsson B, Korsgren O. Isolated human islets trigger an instant blood mediated inflammatory reaction: implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes. Ups J Med Sci 2000;105:125–133.
21. Bennet W, Sundberg B, Groth CG, Brendel MD, Brandhorst D, Brandhorst H, et al. Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes 1999;48:1907–1914.
22. Bühler L, Deng S, O'Neil J, Kitamura H, Koulmanda M, Baldi A, et al. Adult porcine islet transplantation in baboons treated with conventional immunosuppression or a non-myeloablative regimen and CD154 blockade. Xenotransplantation 2002;9:3–13.
23. 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;14:288–297.
24. Cowan PJ. Coagulation and the xenograft endothelium. Xenotransplantation 2007;14:7–12.
25. Lin CC, Chen D, McVey JH, Cooper DK, Dorling A. Expression of tissue factor and initiation of clotting by human platelets and monocytes after incubation with porcine endothelial cells. Transplantation 2008;86:702–709.
26. Glaser CB, Morser J, Clarke JH, Blasko E, McLean K, Kuhn I, et al. Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation. J Clin Invest 1992;90:2565–2573.
27. Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA 1996;93:10212–10216.
28. Taylor FB Jr, Peer GT, Lockhart MS, Ferrell G, Esmon CT. Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 2001;97:1685–1688.
29. Pike RN, Buckle AM, Le Bonniec BF, Church FC. Control of the coagulation system by serpins. Getting by with a little help from glycosaminoglycans. FEBS J 2005;272:4842–4851.
30. 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;82:428–432.
31. Dwyer KM, Deaglio S, Gao W, Friedman D, Strom TB, Robson SC. CD39 and control of cellular immune responses. Purinergic Signal 2007;3:171–180.
32. Shimizu A, Hisashi Y, Kuwaki K, Tseng YL, Dor FJ, Houser SL, et al. Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1,3-galactosyltransferase gene-knockout pigs in baboons. Am J Pathol 2008;172:1471–1481.
33. Cooper DK, Good AH, Koren E, Oriol R, Malcolm AJ, Ippolito RM, et al. Identification of alpha-galactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies: relevance to discordant xenografting in man. Transpl Immunol 1993;1:198–205.
34. Rood PP, Bottino R, Balamurugan AN, Smetanka C, Ayares D, Groth CG, et al. Reduction of early graft loss after intraportal porcine islet transplantation in monkeys. Transplantation 2007;83:202–210.
35. 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;177:127–135.
36. Hering BJ, Kandaswamy R, Harmon JV, Ansite JD, Clemmings SM, Sakai T, et al. Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody. Am J Transplant 2004;4:390–401.
37. Mohanakumar T, Narayanan K, Desai N, Ramachandran S, Shenoy S, Jendrisak M, et al. A significant role for histocompatibility in human islet transplantation. Transplantation 2006;82:180–187.
38. Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 2006;12:682–687.
39. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. In: Immunobiology: the immune system in health and disease. 6th ed. New York: Garland Science; 2005. pp. 55-75.
40. Kues WA, Schwinzer R, Wirth D, Verhoeyen E, Lemme E, Herrmann D, et al. Epigenetic silencing and tissue independent expression of a novel tetracycline inducible system in double-transgenic pigs. FASEB J 2006;20:1200–1202.
41. Cowan PJ, Aminian A, Barlow H, Brown AA, Chen CG, Fisicaro N, et al. Renal xenografts from triple-transgenic pigs are not hyperacutely rejected but cause coagulopathy in non-immunosuppressed baboons. Transplantation 2000;69:2504–2515.
42. Bennet W, Björkland A, Sundberg B, Brandhorst D, Brendel MD, Richards A, et al. Expression of complement regulatory proteins on islets of Langerhans: a comparison between human islets and islets isolated from normal and hDAF transgenic pigs. Transplantation 2001;72:312–319.
43. van der Windt DJ, Bottino R, Casu A, Campanile N, Smetanka C, He J, et al. Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. Am J Transplant 2009;9:2716–2726.
44. Shrivastava S, McVey JH, Dorling A. The interface between coagulation and immunity. Am J Transplant 2007;7:499–506.
45. Contreras JL, 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;53:2804–2814.
46. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000;407:258–264.
47. Moberg L, Korsgren O, Nilsson B. Neutrophilic granulocytes are the predominant cell type infiltrating pancreatic islets in contact with ABO-compatible blood. Clin Exp Immunol 2005;142:125–131.
48. 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;51:1779–1784.
49. Bottino R, Balamurugan AN, Tse H, Thirunavukkarasu C, Ge X, Profozich J, et al. Response of human islets to isolation stress and the effect of antioxidant treatment. Diabetes 2004;53:2559–2568.
50. Hanley S, Liu S, Lipsett M, Castellarin M, Rosenberg L, Tchervenkov J, et al. Tumor necrosis factor alpha production by human islets leads to postisolation cell death. Transplantation 2006;82:813–818.
51. Langford GA, Yannoutsos N, Cozzi E, Lancaster R, Elsome K, Chen P, et al. Production of pigs transgenic for human decay accelerating factor. Transplant Proc 1994;26:1400–1401.
52. Murakami H, Nagashima H, Takahagi Y, Miyagawa S, Fujimura T, Toyomura K, et al. Transgenic pigs expressing human decay-accelerating factor regulated by porcine MCP gene promoter. Mol Reprod Dev 2002;61:302–311.
53. Zhou CY, McInnes E, Copeman L, Langford G, Parsons N, Lancaster R, et al. Transgenic pigs expressing human CD59, in combination with human membrane cofactor protein and human decay-accelerating factor. Xenotransplantation 2005;12:142–148.
54. Lai L, Kolber-Simonds D, Park KW, Cheong HT, Greenstein JL, Im GS, et al. Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science 2002;295:1089–1092.
55. Phelps CJ, Koike C, Vaught TD, Boone J, Wells KD, Chen SH, et al. Production of alpha 1,3-galactosyltransferase-deficient pigs. Science 2003;299:411–414.
56. Tu CF, Hsieh SL, Lee JM, Yang LL, Sato T, Lee KH, et al. Successful generation of transgenic pigs for human decay-accelerating factor and human leucocyte antigen DQ. Transplant Proc 2000;32:913–915.
57. Ramsoondar JJ, Macháty Z, Costa C, Williams BL, Fodor WL, Bondioli KR. Production of alpha 1,3-galactosyltransferase-knockout cloned pigs expressing human alpha 1,2-fucosylosyltransferase. Biol Reprod 2003;69:437–445.
58. Lee S, Chung J, Ha IS, Yi K, Lee JE, Kang HG, et al. Hydrogen peroxide increases human leukocyte adhesion to porcine aortic endothelial cells via NFkappaB-dependent up-regulation of VCAM-1. Int Immunol 2007;19:1349–1359.
59. Hancock WW, Buelow R, Sayegh MH, Turka LA. Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes. Nat Med 1998;4:1392–1396.
60. de Vos P, Faas MM, Strand B, Calafiore R. Alginate-based microcapsules for immunoisolation of pancreatic islets. Biomaterials 2006;27:5603–5617.
61. Stabler CL, Sun XL, Cui W, Wilson JT, Haller CA, Chaikof EL. Surface re-engineering of pancreatic islets with recombinant azido-thrombomodulin. Bioconjug Chem 2007;18:1713–1715.
62. Kin T, O'Neil JJ, Pawlick R, Korbutt GS, Shapiro AM, Lakey JR. The use of an approved biodegradable polymer scaffold as a solid support system for improvement of islet engraftment. Artif Organs 2008;32:990–993.
63. Berman DM, O'Neil JJ, Coffey LC, Chaffanjon PC, Kenyon NM, Ruiz P Jr, et al. Long-term survival of non-human primate islets implanted in an omental pouch on a biodegradable scaffold. Am J Transplant 2009;9:91–104.
64. Dufour JM, Rajotte RV, Zimmerman M, Rezania A, Kin T, Dixon DE, et al. Development of an ectopic site for islet transplantation, using biodegradable scaffolds. Tissue Eng 2005;11:1323–1331.
65. Hering BJ, Wijkstrom M, Graham ML, Hårdstedt 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;12:301–303.
66. 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;12:304–306.
67. Dufrane D, Goebbels RM, Saliez A, Guiot Y, Gianello P. Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept. Transplantation 2006;81:1345–1353.
Similar articles

Current Status and Future Perspectives of Xenotransplantation

Implications of Calcineurin/NFAT Inhibitors' Regulation of Dendritic Cells and Innate Immune Cells in Islet Xenotransplantation

Current Status of Solid Organ Xenotransplantation

Pancreas and Islet Transplantation in Diabetes

Erratum: Increase in Anti-Gal IgM Level is Associated With Early Graft Failure in Intraportal Porcine Islet Xenotransplantation