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.  https://doi.org/10.4285/jkstn.2009.23.3.214
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: curie@snu.ac.kr )
Received December 28, 2009; Accepted December 28, 2009.

Abstract

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

Figures


Fig. 1
Treatment of diabetes mellitus-strength & weakness.
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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.

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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.

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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.

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