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Originally published online as doi:10.1189/jlb.1104649 on February 22, 2005

Published online before print February 22, 2005
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(Journal of Leukocyte Biology. 2005;77:587-597.)
© 2005 by Society for Leukocyte Biology

Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts

Neal R. Barshes, Samuel Wyllie and John A. Goss1

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas

1 Correspondence: Baylor College of Medicine Liver Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 6550 Fannin, Suite 1628, Houston, TX 77030. E-mail: jgoss{at}bcm.tmc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 INTRACELLULAR MEDIATORS OF...
 THE ROLE OF INFLAMMATORY...
 THE ROLE OF SINUSOIDAL...
 HEPATOCYTES AND PANCREATIC ISLET...
 NATURAL PROTECTIVE MECHANISMS
 SUMMARY
 REFERENCES
 
Recent advances in clinical protocols have improved the outcomes of pancreatic islet transplantation (PIT), yet PIT recipients typically require pancreatic islet grafts derived from multiple donors to achieve insulin independence. This along with experimental models of syngeneic PIT, showing that up to 60% of pancreatic islet tissue undergoes apoptosis within the first several days post-transplantation, strongly suggest the involvement of nonalloantigen-specific, inflammatory events in partial destruction of the graft following PIT. Interleukin-1ß appears to be among the most important inflammatory mediators, causing pancreatic islet dysfunction and apoptosis through the up-regulation of inducible nitric oxide (NO) synthase and cyclooxygenase-2. Kupffer cells secrete many molecules, including cytokines, NO, and free radicals, which are known to be directly toxic to the pancreatic islets, and depletion or inhibition of Kupffer cells improves outcomes following experimental PIT. Immediately after transplantation, the pancreatic islets are perfused only by portal vein blood until the process of angiogenesis restores arterial blood flow some 7–10 days later. This delayed vascularization may have implications for the expression of leukocyte adhesion molecules, the effects of free radicals, and the role of ischemia-reperfusion injury. Finally, in the immediate post-transplant period, hepatocytes may contribute to pancreatic islet injury through the production of NO. This paper reviews literature regarding the inflammatory events that follow PIT as well as the pathogenesis of diabetes and the pathophysiology of hepatic ischemia-reperfusion and their relation to the survival and function of intrahepatic pancreatic islet grafts.

Key Words: Kupffer cell • ischemia-reperfusion • cytokines • portal vein


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
INTRACELLULAR MEDIATORS OF...
 THE ROLE OF INFLAMMATORY...
 THE ROLE OF SINUSOIDAL...
 HEPATOCYTES AND PANCREATIC ISLET...
 NATURAL PROTECTIVE MECHANISMS
 SUMMARY
 REFERENCES
 
Evidence for inflammation-mediated destruction of the pancreatic islets
The recent clinical success of pancreatic islet transplantation (PIT) as a treatment for insulin-dependent diabetes mellitus [1 2 3 ] is the culmination of research initiated some 30 years ago [4 ]. This recent success was made possible only through advancements in the procurement of pancreatic islets, immunosuppression of pancreatic islet recipients, and an increase in the number of pancreatic islets transplanted. One of the lessons learned is that many more pancreatic islets are needed to successfully restore glucose homeostasis than one might expect. The average human pancreas has between 300,000 and 1.5 million pancreatic islets, and it has been estimated that only 60% of this pancreatic islet cell mass is needed to maintain a normal glucose metabolism [5 ]. In spite of this, pancreatic islets derived from multiple donors are usually needed to achieve insulin independence [1 , 2 , 6 ], and only rarely is insulin independence achieved after transplantation with pancreatic islets from a single donor [7 ]. Although there is some loss in yield when isolating the pancreatic islets from the procured whole pancreas, accruing evidence suggests that a higher-than-expected ß cell mass is needed to make up for pancreatic islet death that occurs in the post-transplant period [8 9 10 ].

Although many mechanisms, including alloantigen-specific, immune-mediated destruction, may explain this partial graft loss, syngeneic transplants demonstrate that much of the loss may be a result of inflammatory events [11 , 12 ]. Indeed, up to 60% of the ß cell mass undergoes apoptosis in experimental models of syngeneic PIT, and half of this loss occurs within the first 3 days after transplantation. This rate of apoptosis following PIT is 10 times higher than the rate seen in the native pancreatic islets [13 ]. Furthermore, the molecules and cells that are active following PIT are suggestive of an alloantigen-nonspecific, inflammatory process. In particular, the inflammatory cytokines interleukin-1ß (IL-1ß), interferon-{gamma} (IFN-{gamma}), and tumor necrosis factor {alpha} (TNF-{alpha}) are elevated following PIT [9 ], and tissue macrophages also appear involved in mediating cellular injury to the recently transplanted pancreatic islets [14 , 15 ]. Administration of drugs that inhibit cytokine actions or macrophage function has been found to improve function of the pancreatic islets after transplantation [16 , 17 ].

The process of pancreatic islet dysfunction and apoptosis has been studied in the context of the pathogenesis of types I and II diabetes mellitus [18 ], death of pancreatic islets in culture [19 ], and post-transplant pancreatic islet primary nonfunction [20 ], and much of our understanding of the effects of inflammatory cytokines and free radicals is derived from these studies. Recent studies have focused on the nonalloantigen-specific, inflammatory events occurring after PIT, further defining the processes that may result in dysfunction and apoptosis of the pancreatic islets.

In this article, we review the clinical and experimental studies that have focused on the inflammatory process following PIT and how it affects the function and survival of the graft. We will also review selected studies of the pathogenesis of insulin-dependent diabetes mellitus and the pathophysiology of hepatic ischemia-reperfusion as it relates to PIT. The cascade of intracellular events taking place in the pancreatic islets will be reviewed first, as this is critical to understanding the subsequent review of how surrounding cells in the hepatic sinusoids may initiate this process. Finally, a brief review of natural, anti-inflammatory, protective mechanisms present in the pancreatic islets will be presented.


   INTRACELLULAR MEDIATORS OF DYSFUNCTION AND APOPTOSIS/NECROSIS IN THE PANCREATIC ISLETS
TOP
 ABSTRACT
 INTRODUCTION
 INTRACELLULAR MEDIATORS OF...
THE ROLE OF INFLAMMATORY...
 THE ROLE OF SINUSOIDAL...
 HEPATOCYTES AND PANCREATIC ISLET...
 NATURAL PROTECTIVE MECHANISMS
 SUMMARY
 REFERENCES
 
An explanation of the intracellular events that lead to dysfunction and death of the pancreatic islets is necessary to understand the interactions that may occur between the transplanted pancreatic islets and the other cells of the hepatic sinusoids. There are several mediators that have been found to cause dysfunction and/or cellular death of the pancreatic islets including inflammatory cytokines such as IL-1ß, TNF-{alpha}, and IFN-{gamma}; nitric oxide (NO); prostaglandins (PGs); and reactive oxygen intermediates (ROIs), such as superoxide radical and hydrogen peroxide. The effects that free radicals, cytokines, and NO have on the pancreatic islets have been studied in the context of pathogenesis of diabetes mellitus [21 ].

IL-1ß
IL-1ß appears to be among the most important cytokine mediators of pancreatic islet injury [21 ], and its role in the process of dysfunction of the pancreatic islets has been studied extensively (Table 1 ). IL-1ß is secreted by activated macrophages (including Kupffer cells) [25 ] and neutrophils [26 ]. Through a cascade of intracellular events, IL-1ß causes a decrease in glucose-stimulated insulin biosynthesis and secretion [27 ] and in high doses, apoptosis of the pancreatic islets [26 ].


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  		Table 1. Effects of IL-1ß on the Pancreatic Islets

 
The binding of IL-1ß to the IL-1ß receptor (IL-1ßR) on the pancreatic islet cell surface is the first step in a series of events that leads to gene transcription. This binding leads to IL-1 receptor-associated kinase (IRAK) [28 ] activating the TNF receptor-associated factor 6 (TRAF6) [29 , 30 ] (Fig. 1 ). TRAF6 activation then leads to phosphorylation, ubiquitination, and ultimate degradation of I{kappa}B in the 26S proteasome complex [31 , 32 ]. NF-{kappa}B is then able to dissociate from the inhibitory subunit I{kappa}B and translocate from the cytoplasm to the nucleus [33 ]. In the nucleus, NF-{kappa}B binds to DNA, regulating the transcription of a multitude of genes, including IL-1, IL-6, TNF-{alpha} [24 ], ICAM-1 [34 , 35 ], VCAM-1, ELAM-1 [22 ], iNOS [36 ], PGE2, and EP3 mRNA [16 , 23 ]. Thus, it appears that NF-{kappa}B mediates much of the effect that IL-1ß has on the pancreatic islet [37 ].



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  		Figure 1. Schematic diagram demonstrating the intracellular cascade of events that occur in the pancreatic islet after stimulation by IL-1ß. I{kappa}B, Inhibitor of {kappa}B; COX, cyclooxygenase; iNOS, inducible NO synthase; VCAM-1, vascular cell adhesion molecule-1; ELAM-1, endothelial leukocyte adhesion molecule-1.

 
IL-1ß also leads to down-regulation of GLUT2 and glucokinase mRNA expression, enzymes that transport and phosphorylate glucose in the pancreatic islet, respectively [38 ]. GLUT2 is known to be an essential component in the glucose-response apparatus of pancreatic ß cells, and down-regulation of this molecule impairs the ability of the pancreatic islet to detect elevated serum levels of glucose and respond appropriately [39 ]. Finally, IL-1ß can also lead to cell membrane damage DNA strand breaks, although this event may be mediated by NO [40 ].

Levels of IL-1ß increase significantly following experimental PIT [9 ] as well as following whole pancreas allograft ischemia-reperfusion injury [41 ]. Experimental models have shown that inhibition of IL-1ß release may ameliorate injury to the pancreatic islets, and circulating anti-IL-1ß antibodies or circulating IL-1ßR prevent type I diabetes [42 ]. Attempts at ameliorating the effects of IL-1ß by administration of sodium salicylate, which inhibits IL-1ß-mediated induction of COX-2 gene expression, also result in improved function of pancreatic islets [16 ]. In animal models of PIT and diabetes, IL-1ß alone will stimulate NO and PG production. In humans, however, it appears that IL-1ß must act in combination with TNF-{alpha} and/or IFN-{gamma} [28 , 43 , 44 ].

Although there is some evidence that NF-{kappa}B is activated in pancreatic islets undergoing apoptosis [45 ], conflicting accounts of the role NF-{kappa}B in cell death exist [46 , 47 ]. Aspirin and sodium salicylate inhibit NF-{kappa}B activation [33 ] and may represent pharmacological means to manipulate NF-{kappa}B activation after PIT.

NO and iNOS
Cytokine-induced production of NO is an important event in primary nonfunction of transplanted pancreatic islet grafts [48 ]. It is clear that much of the dose-dependent inhibition of glucose-stimulated insulin secretion caused by IL-1ß is mediated by NO [10 , 49 50 51 ], although other mechanisms are involved [44 ]. NO decreases insulin synthesis by the inhibition of the Krebs cycle enzyme aconitase [52 ]. NO may also cause cell death by inducing DNA strand breaks [53 ], an event that leads to apoptosis [54 ].

As mentioned earlier, the binding of IL-1ß to IL-1ßR results in the translocation of NF-{kappa}B to the nucleus [33 ], leading to the up-regulation of iNOS [36 ]. This up-regulation is likely a result of the presence of a NF-{kappa}B-binding site and multiple IFN-response elements on the human iNOS promoter [55 ]. Expression of iNOS is up-regulated after PIT [56 ]. Competitive inhibition of NOS by L-N-G-monomethyle-arginine results in decreased NO production by the pancreatic islets [44 , 56 ] and enhances the achievement of euglycemia after PIT [27 ]. Although the pancreatic islets produce increased amounts of NO following PIT, other cells (namely, Kupffer cells and hepatocytes) also produce NO. At this time, it is unclear how much the production of NO from each cell type contributes to injury and cell death of the transplanted pancreatic islets.

COX-2 and PGE2
The enzyme COX seems to have an important role in regulating pancreatic islet insulin secretion. In most cell types, COX-1 is constitutively expressed, and COX-2 is induced only under conditions of stress [57 ]. In contrast, COX-2 expression predominates over COX-1 expression in cells of the pancreatic islet at basal and stimulated conditions [58 ]. Indeed, under normal, nonstimulated conditions, the pancreatic islets generate significant levels of COX-2 [58 ]. The COX-2 promoter has binding site NF-{kappa}B, IL-6, activated protein-1, and a cyclic adenosine monophosphate (cAMP)-response element [59 ]. Exposure to IL-1ß, TNF-{alpha}, or IFN-{gamma} results in a further up-regulation of COX-2 mRNA, and levels peak 2–4 h after exposure and waning by 24 h following such stimulation [58 ].

COX-2 (as well as COX-1) generates prostanoids from arachidonic acid, including PGD2, PGE2, PGF2{alpha}, PGI2, and thromboxane A2 (TXA2) [60 ]. PGE2 is a potent inhibitor of glucose-induced insulin secretion and works by binding to its cell-surface receptor, EP. There are at least four subtypes of the EP receptor (EP1–EP4), many having opposing effects on the intracellular signaling pathway using adenylate cyclase. The manner in which these receptor subtypes function to inhibit insulin secretion is not well understood [60 ], but it appears that the EP3 subtype, which decreases cAMP in pancreatic islets, may be the most important subtype in this inhibition of insulin secretion [23 ]. It is notable that the EP promoter has a NF-{kappa}B-binding site [61 ], and inhibition of NF-{kappa}B with sodium salicylate results in decreased expression of EP3 [16 ]. Administration of dexamethasone and sodium salicylate decreases COX-2 levels in the pancreatic islets [16 , 60 ]. Experimental evidence suggests that in vitro exposure of pancreatic islets to COX-2-specific inhibitors will result in improved in vivo pancreatic islet function after subsequent transplantation [17 ]. Not all PGs are injurious to the pancreatic islets, however, and some PGs may in fact be beneficial to function and survival after transplantation. The PGI2 analog beraprost sodium, for example, improves pancreatic islet viability during the pancreatic islet isolation procedure [62 ] and after transplantation [63 ].

ROIs
Cytotoxic products derived from oxygen metabolism are formed after tissue reperfusion, catalyzed in part by xanthine oxidase [64 ]. Reperfusion leads to xanthine oxidase-mediated production of superoxide radical and hydrogen peroxide. Superoxide can participate in a further reaction with molecular iron or copper to produce hydroxyl radical, an even more reactive oxygen species [65 ]. These oxygen-free radicals attack lipids, proteins, and nucleic acids, leading to an increase capillary permeability, disrupt cellular membranes, and degrade nucleic acids in the nucleus and cytoplasm. If the severity of injury is marked, cellular death may occur [66 ].

The pancreatic islet cells appear especially susceptible to reperfusion injury and oxidative stress. Compared with other cells, pancreatic ß cells express lower levels of the antioxidants glutathione peroxidase, catalase, thioredoxin, and superoxide dismutase [67 68 69 70 ]. In experimental models of diabetes, increasing these antioxidant levels confers some protection against IL-1ß- and NO-induced cytotoxicity to the pancreatic islets [70 71 72 ].

Although well-studied in the context of diabetes mellitus, the role of free radical-mediated injury following PIT has not been well-studied. One experimental study of PIT examined graft function after PIT when animals were administered antioxidants. One group received ß-carotene, ascorbic acid, {alpha}-tocopherol, selenium, and vitamin A, a second group received vitamins E and C, and a third group received no antioxidants. No benefit was seen from the administration of antioxidants [73 ].


   THE ROLE OF INFLAMMATORY CELLS
TOP
 ABSTRACT
 INTRODUCTION
 INTRACELLULAR MEDIATORS OF...
 THE ROLE OF INFLAMMATORY...
THE ROLE OF SINUSOIDAL...
 HEPATOCYTES AND PANCREATIC ISLET...
 NATURAL PROTECTIVE MECHANISMS
 SUMMARY
 REFERENCES
 
There are three types of inflammatory cells that may have some role in inflammation-mediation injury of the pancreatic islets: Kupffer cell, "resident" macrophages of the pancreatic islets, and neutrophils. Although the role of the neutrophil has been well-studied in the context of hepatic ischemia-reperfusion, its role following PIT has not been studied, and it will be omitted from this discussion.

Kupffer cells
An important mediator of inflammation in the hepatic sinusoids is the Kupffer cell, which is the resident macrophage of the liver and is present in large numbers, comprising ~80% of the total number of tissue macrophages in humans [74 ]. When activated, Kupffer cells can injure other cells in two ways: by release of free radicals and by secretion of inflammatory cytokines. Indeed, the list of molecules secreted by Kupffer cells following activation is lengthy and is notable for many known toxic metabolites: peptide mediators, such as IL-1ß, IL-6, TNF-{alpha}, IFN-{alpha}; enzymes, such as collagenase, elastase, angiogenesis factors; several coagulation factors; complement; arachionic acid metabolites, such as TXA2, leukotrienes, platelet-activating factor, and PGs; and reactive oxygen and nitrogen species, such as superoxide, hydrogen peroxide, and nitric oxide [9 , 75 , 76 ].

Ischemia-reperfusion injury of the liver activates the Kupffer cells [77 ], and this activation has been implicated as the primary, early step in initiating the inflammatory processes of liver ischemia-reperfusion. Kupffer cells appear to be activated following PIT also, as levels of Kupffer cell-secreted cytokines IL-1ß and TNF-{alpha} are elevated following PIT (Fig. 2 ). Macrophage depletion prevents this elevation [9 ]. However, the mechanism of Kupffer cell activation following PIT is not yet fully understood. In vitro experiments suggest that the pancreatic islets may directly stimulate the Kupffer cells by some yet-unidentified, soluble factor [78 ]. A final pathway by which Kupffer cells become activated may exist via activation of the sinusoidal endothelium. In the context of liver ischemia/reperfusion, stimuli that cause activation of the sinusoidal endothelial cells will also initiate nonspecific inflammatory responses [79 ]. Intraportal infusion of pancreatic islets does cause injury to the sinusoidal endothelium [9 ], suggesting that this pathway may also have a role in PIT.



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  		Figure 2. Schematic diagram showing known and hypothesized interactions between the pancreatic islets and cells of the hepatic sinusoids.

 
Other factors involved in PIT may have a role in the activation of Kupffer cells. Many of the collagenase preparations that have been used in the process of isolating and separating pancreatic islets from acinar or nonendocrine tissue have been shown to contain varying amounts of endotoxin, and the endotoxin contaminant transplanted along with the pancreatic islets induces proinflammatory cytokine production by host macrophages and pancreatic islet cells [80 ]. Acinar (i.e., exocrine) cell contaminants in the pancreatic islet grafts may also incite Kupffer cells. When transplanted along with pancreatic islets, acinar tissue undergoes necrosis [81 ]. An experimental study examining the effects of exocrine tissue contamination on PIT found a direct correlation between the amount of exocrine tissue contamination and post-transplant necrosis, foreign body giant cell formation, and decreased viability of the pancreatic islets. The authors proposed that one possible mechanism to explain this was that exocrine cell death and subsequent enzyme release stimulated inflammatory processes, which ultimately, led to death of the pancreatic islet cells [81 ].

Resident macrophages within the pancreatic islets
Resident macrophages residing within pancreatic islets appear to be important mediators of pancreatic islet injury and destruction [82 83 84 ]. In response to proinflammatory stimuli such as TNF-{alpha}, lipopolysaccharide (LPS), or IFN-{gamma}, these resident macrophages are an important intra-islet source of IL-1 [85 ] and iNOS production [84 ]. Although resident macrophages may be an important source of IL-1, a more recent study has demonstrated that the pancreatic islet ß cell may be capable of producing IL-1 in response to IFN-{gamma} stimulation, independent of resident macrophages [86 ]. Nonetheless, culture conditions, which are selectively toxic to these resident macrophages, lead to decreased cytokine-stimulated iNOS expression and subsequent NO production [85 ]. Indeed, after 7 days in such culture conditions, exposure to IFN-{gamma} causes no cytotoxicity; in contrast, islets not depleted of macrophages are destroyed [87 ]. Finally, TNF-{alpha} does not lead to NO production or cytotoxicity to individual ß cells separated from an intact islet [50 , 85 ].


   THE ROLE OF SINUSOIDAL ENDOTHELIAL CELLS
TOP
 ABSTRACT
 INTRODUCTION
 INTRACELLULAR MEDIATORS OF...
 THE ROLE OF INFLAMMATORY...
 THE ROLE OF SINUSOIDAL...
HEPATOCYTES AND PANCREATIC ISLET...
 NATURAL PROTECTIVE MECHANISMS
 SUMMARY
 REFERENCES
 
All organs critically depend on blood flow for the delivery of nutrients and for the removal of byproducts of metabolism. The pancreatic islets are particularly well-perfused: Although they make up only 1% of the weight of the pancreas, the pancreatic islets receive 5–15% of the blood flow of the pancreas [88 , 89 ]. During the process of mechanical and enzymatic digestion, the pancreatic islets are separated from their blood supply [90 ]. When transplanted via portal vein infusion, the pancreatic islets are embolized into the portal vein and its radicals, and they eventually rest in the hepatic presinusoids capillaries [9 , 91 ].

During the first several weeks post-transplantation, the pancreatic islets are exposed only to portal venous blood [92 ]. During the first 24–48 h after transplantation, the capillary bed in the pancreatic islet collapses and is expelled from the islet [93 ], leaving minimal or no intraislet (i.e., donor) endothelial cells [94 ]. VEGF is up-regulated within 24–48 h after transplantation [95 ]. Perfusion of the transplanted pancreatic islets does not occur until after the process of angiogenesis has established new capillaries of donor origin [96 ]. Angiogenesis may start as early as 7 days post-transplantation, and within 10–14 days, the process is well under way [97 , 98 ]. After engraftment, the majority of pancreatic islets is drained by the portal vein [92 ], although some may be drained by the hepatic veins [12 ]. So, in contrast to the transplantation of solid organs, which are reperfused immediately upon the completion of the arterial and venous anastamoses (i.e., during the transplant operation), PIT may be more similar to skin and cornea transplants in that no direct blood flow is established at the time of transplantation. There may be many consequences of this delayed revascularization for the pancreatic islet function in general and for a post-transplant inflammatory event in particular.

Hypoxia and inflammation after PIT
Perhaps the most obvious implication of this delayed arterial perfusion is that the pancreatic islets are temporarily hypoxic. The oxygen saturation and content of the hepatic artery average 96% and 15.2 vol%, respectively, and the oxygen saturation and content of the portal vein average only 85% and 13.2 vol%, respectively, in normal individuals [99 ]. Experimental studies have shown that the oxygen tension of pancreatic islets transplanted in the liver, spleen, or under the renal capsule was only a fraction of the oxygen tension of native pancreatic islets or of pancreatic islets in a whole pancreas graft [100 101 102 ]. It is interesting that this decreased oxygen tension lasts up to 9 months post-transplant, well past the time required for revascularization of the pancreatic islets [103 ]. Hypoxia can cause pancreatic islet death and dysfunction [104 , 105 ]. The insulin-producing ß cells, found in higher concentrations at the center of the pancreatic islets, may be at increased risk because of the limited diffusion of oxygen and nutrients that is inherent to the spherical form of the pancreatic islets [106 ]. The relationship between hypoxemia and insulin secretion and blood flow is not completely understood, but it appears that significant decreases in oxygen tension will diminish insulin secretion [104 ]. Furthermore, administration of hyperbaric oxygen to animal models of PIT improves graft function [107 ].

This relative hypoxia may, conversely, have some protective effects with respect to inflammation-mediated cellular injury. It is known that relatively little injury is seen in most organs during the ischemic phase of ischemia reperfusion. Indeed, more severe injury is apparent only upon reperfusion [108 ], and hypoxic reperfusion is known to abrogate reperfusion injury in other organs [109 , 110 ]. Although tissue ischemia alone may be injurious, the reintroduction of oxygen after reperfusion is more harmful [108 ]. Molecular oxygen is the source of reactive oxygen metabolites, which are responsible for the majority of the tissue damage seen during the sequence of ischemia and reperfusion [109 ].

Adhesion molecules and chemokines
In addition to modulating blood perfusion through vasoconstriction and vasodilation, the venous endothelium (such as that found in the hepatic sinusoids) plays an important role in the inflammatory process by recruiting blood cells into surrounding tissue. Activation of sinusoidal endothelial cells stimulates the release of leukocyte rolling receptors from the pool of preformed receptors present in the Wiebel-Palade bodies of venous endothelial cells [111 ]. Expression of adhesion molecules such as P-selectin, E-selectin, and ICAM-1 leads to leukocyte adherence, facilitating the diapedesis and infiltration of neutrophils and macrophages into the surrounding tissue [112 , 113 ].

ICAM-1 is a cell-surface molecule involved in the transendothelial migration of leukocytes and macrophages. Leukocyte function-associated antigen-1 and macrophage differentiation antigen-1, found on leukocytes and macrophages, bind ICAM-1. Blocking ICAM-1 ligand binding in experimental models of PIT, through anti-ICAM-1 antibodies or through ICAM-1 antisense oligodeoxynucleotides, prevents rejection of the grafts [114 , 115 ]. Although no postcapillary venous endothelium is perfused until after angiogenesis re-establishes direct blood flow to the pancreatic islets, it seems that the pancreatic islets themselves can also express ICAM-1 after stimulation with IFN-{gamma}, hypoxia, or time in culture [35 , 116 , 117 ]. So, although the pancreatic islets may express ICAM-1 following PIT, the delay in vascularization of the islets may ameliorate leukocyte infiltration by decreasing the amount of leukocyte adhesion molecules expressed. Finally, the endothelial lining of the eventual islet graft microvasculature has been shown to be of host (i.e., recipient) origin [96 ], a feature that may have important implications for host acceptance of an allogeneic pancreatic islet graft.

There appears to be some relationship between secretion of chemokines and inflammatory processes in the pancreatic islets. Monocyte chemoattractant protein-1 (MCP-1) is a chemotactic protein constitutively secreted by normal human pancreatic islet cells. mRNA and protein-level expression of MCP-1 is increased by IL-1ß and LPS [118 ] through a NF-{kappa}B-dependent, NO-independent mechanism [119 ]. There is some evidence that human PIT recipients that produce low levels of MCP-1 following transplantation have a higher rate of insulin independence than those recipients that produce high levels of MCP-1 [118 ].

Prothrombotic events following PIT
The hepatic sinusoidal endothelium becomes prothrombotic following ischemia-reperfusion injury. Kupffer cell secretion of TNF-{alpha} and IL-1ß leads to the increased endothelial cell factor VII expression, thromboplastin expression, and platelet activation factor, further inducing platelet adhesion [120 , 121 ]. Hypoxia also contributes to the production of a prothrombotic microenvironment by the suppression of thrombomodulin synthesis and the stimulation of factor X release [122 ].

Tissue factor, a membranous glycoprotein, is capable of initiating the extrinsic coagulation pathway via activation of factor VII/VIIa. Tissue factor is expressed by Kupffer cells, hepatic sinusoidal endothelial cells, and pancreatic islets only after stimulation with IL-1ß, TNF-{alpha}, LPS, or immune complexes [123 , 124 ]. Expression of tissue factor is also increased following exposure to TNF-{alpha} [125 ]. Following transplantation, the expression of tissue factor by the pancreatic islets is increased. This may generate thrombin, leading to the activation and aggregation of platelets and the ultimate formation of a fibrin capsule around the islets [126 , 127 ], similar to what may be seen in the hepatic sinusoids of a liver allograft with severe, primary nonfunction [128 , 129 ]. It has also been proposed that the pancreatic islets themselves contribute to the fibrin capsule formation by inducing an "instant blood-mediated inflammatory reaction," which results in the activation of platelets and formation of thrombin and fibrin [130 ]. In vitro inhibition of thrombin formation decreases this thrombotic reaction [131 ].


   HEPATOCYTES AND PANCREATIC ISLET CELLS
TOP
 ABSTRACT
 INTRODUCTION
 INTRACELLULAR MEDIATORS OF...
 THE ROLE OF INFLAMMATORY...
 THE ROLE OF SINUSOIDAL...
 HEPATOCYTES AND PANCREATIC ISLET...
NATURAL PROTECTIVE MECHANISMS
 SUMMARY
 REFERENCES
 
The secreted hormones of the pancreatic islets may promote growth of hepatocytes. Starzl et al. [132 ] were the first to establish insulin as the primary hepatotrophic factor present in the portal blood flow. The presence of pancreatic islets in the hepatic sinusoids as seen following PIT results in a localized increased insulin. Following this localized increase in insulin, glycogen deposition and microvesicular steatosis are seen in a periportal distribution following intraportal infusion of pancreatic islets in humans and nonhuman primates [133 , 134 ].

Hepatocytes, conversely, may injure the pancreatic islets in the immediate post-transplant period by the production of NO (Fig. 2) . NOS mRNA is not expressed in unstimulated hepatocytes, but hepatocyte stimulation by IL-1, TNF-{alpha}, and IFN-{gamma} leads to an up-regulation of hepatocyte NOS mRNA and a 20- to 30-fold increase in production of NO [48 ]. Pancreatic islets can stimulate the production of NO by hepatocytes and Kupffer cells in vitro [56 , 135 ]. Unstimulated pancreatic islets induce minimal hepatocyte NO production, and hepatocyte production of NO following exposure to inflammatory cytokines IL-1, TNF-{alpha}, and IFN-{gamma} is only moderately increased. However, when hepatocytes are exposed to IL-1, TNF-{alpha}, and IFN-{gamma} in the presence of pancreatic islets, hepatocyte production of NO is increased significantly [48 ]. It has been suggested that this secretion of NO in vivo may the most important factor leading to failure of clinical PIT, and the liver has been identified as the sole source of NO production following PIT. Indeed, the amount of NO produced in an animal model of PIT correlates with the pancreatic islet mass transplanted [56 ].


   NATURAL PROTECTIVE MECHANISMS
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 ABSTRACT
 INTRODUCTION
 INTRACELLULAR MEDIATORS OF...
 THE ROLE OF INFLAMMATORY...
 THE ROLE OF SINUSOIDAL...
 HEPATOCYTES AND PANCREATIC ISLET...
 NATURAL PROTECTIVE MECHANISMS
SUMMARY
 REFERENCES
 
Hemo oxygenase-1 (HO-1), also known as heat shock protein 32, is an inducible enzyme that is responsible for the degradation of heme into biliverdin, iron, and carbon monoxide (CO) [136 ]. HO-1 is expressed in many cell lines during stress-related stimuli, such as exposure to IL-1ß [137 ] or NO [138 ]. In vitro stimulation of pancreatic ß cells with TNF-{alpha} [139 ] or IL-1ß [140 ] causes up-regulation of HO-1. Up-regulation in the pancreatic islets is seen during islet isolation [141 ]. It appears that HO-1 has an antiapoptotic function on pancreatic ß cells through a mechanism involving activation of the p38 mitogen-activated protein kinase (MAPK) pathway signal transduction pathway, and overexpression of HO-1 is protective against apoptosis [139 , 142 ].

Some of the breakdown products of heme oxygenase products, namely bilirubin and CO, may also serve as antioxidants. Bilirubin scavenges peroxyl radicals in the serum and plasma, preventing oxidation of membranes [143 ]. CO appears to have antiapoptotic and anti-inflammatory function in pancreatic ß cells and endothelial cells that is independent of HO-1. It is unclear whether the antiapoptotic effect of CO is mediated through activation of guanylate cyclase and cyclic guanosine monophosphate-dependent kinase [144 ], the p38 MAPK pathway [145 ], or both, but it appears that CO exerts its as potent anti-inflammatory effects in vitro and in vivo by inhibition of TNF-{alpha} production [145 ]. Brief exposure of isolated, purified murine pancreatic islets to CO while in culture improved function of the pancreatic islets following subsequent transplantation [144 ].

IL-10 has many important anti-inflammatory properties, including the inhibition of IFN-{gamma} release from macrophages. Nonobese diabetic mice with an IL-10 deficiency are especially prone to the development of diabetes [146 ], and administration of recombinant IL-10 confers protection against the development of diabetes in these mice [147 ]. These anti-inflammatory properties do not seem static, however, and it appears that IL-10 may accelerate the development of autoimmune diabetes at some earlier stages in the disease. Administration of IL-10 to animals that have undergone syngeneic PIT has been investigated, and conflicting results regarding the effect on survival of the transplanted pancreatic islets have been reported [148 , 149 ].


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 INTRACELLULAR MEDIATORS OF...
 THE ROLE OF INFLAMMATORY...
 THE ROLE OF SINUSOIDAL...
 HEPATOCYTES AND PANCREATIC ISLET...
 NATURAL PROTECTIVE MECHANISMS
 SUMMARY
REFERENCES
 
Experimental models of syngeneic PIT have shown that up to 60% of pancreatic islet tissue undergoes apoptosis within the first several days post-transplantation. IL-1ß is the most important cytokine mediator of inflammation, leading to the production of iNOS and COX-2. Although the pancreatic islets seem especially susceptible to oxidative injury, the role of free radicals after PIT is not clearly defined at this time. Kupffer cells, with the ability to secrete IL-1ß, TNF-{alpha}, IFN-{gamma}, NO, and free radicals, are clearly important to the inflammatory process that follows PIT. The sinusoidal endothelium may contribute to inflammation through the up-regulation of leukocyte adhesion molecules and by creating a prothrombotic environment. Some natural mechanisms exist for protection of the pancreatic islets against inflammatory injury (Table 2 ). Further understanding of these inflammatory events and treatment options to ameliorate this process may further improve outcomes of PIT.


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  		Table 2. A Summary of Observed and Purported Interactions between Transplanted Pancreatic Islets and the Cells of the Hepatic Sinusoids

 

Received November 5, 2004; revised January 14, 2005; accepted January 17, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 INTRACELLULAR MEDIATORS OF...
 THE ROLE OF INFLAMMATORY...
 THE ROLE OF SINUSOIDAL...
 HEPATOCYTES AND PANCREATIC ISLET...
 NATURAL PROTECTIVE MECHANISMS
 SUMMARY
 REFERENCES
 

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