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Originally published online as doi:10.1189/jlb.1104649 on 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


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ABSTRACT
 
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


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INTRODUCTION
 
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.


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INTRACELLULAR MEDIATORS OF DYSFUNCTION AND APOPTOSIS/NECROSIS IN THE PANCREATIC ISLETS
 
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 ].


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THE ROLE OF INFLAMMATORY CELLS
 
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 ].


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THE ROLE OF SINUSOIDAL ENDOTHELIAL CELLS
 
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 ].


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HEPATOCYTES AND PANCREATIC ISLET CELLS
 
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 ].


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NATURAL PROTECTIVE MECHANISMS
 
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 ].


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SUMMARY
 
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.


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REFERENCES
 
    1
  1. Shapiro, A. M., Lakey, J. R., Ryan, E. A., Korbutt, G. S., Toth, E., Warnock, G. L., Kneteman, N. M., Rajotte, R. V. (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen N. Engl. J. Med. 343,230-238[Abstract/Free Full Text]
    2. 2
  2. Barshes, N. R., Lee, T., Goodpasture, S., Brunicardi, F. C., Alejandro, R., Ricordi, C., Soltes, G., Barth, M., Hamilton, D., Goss, J. A. (2004) Achievement of insulin independence via pancreatic islet transplantation using a remote isolation center: a first-year review Transplant. Proc. 36,1127-1129[CrossRef][Medline]
    3. 3
  3. Osama, G. A., Chamsuddin, A., Fraga, D., Fisher, J., Lo, A. (2004) Insulin independence achieved using the transmesenteric approach to the portal vein for islet transplantation Transplantation 77,309-311[CrossRef][Medline]
    4. 4
  4. Ballinger, W. F., Lacy, P. E. (1972) Transplantation of intact pancreatic islets in rats Surgery 72,175-186[Medline]
    5. 5
  5. London, N. J., Robertson, G. S., Chadwick, D. R., Johnson, P. R., James, R. F., Bell, P. R. (1994) Human pancreatic islet isolation and transplantation Clin. Transplant. 8,421-459[Medline]
    6. 6
  6. Goss, J. A., Schock, A. P., Brunicardi, F. C., Goodpastor, S. E., Garber, A. J., Soltes, G., Barth, M., Froud, T., Alejandro, R., Ricordi, C. (2002) Achievement of insulin independence in three consecutive type-1 diabetic patients via pancreatic islet transplantation using islets isolated at a remote islet isolation center Transplantation 74,1761-1766[CrossRef][Medline]
    7. 7
  7. Markmann, J. F., Deng, S., Huang, X., Desai, N. M., Velidedeoglu, E. H., Lui, C., Frank, A., Markmann, E., Palanjian, M., Brayman, K., Wolf, B., Bell, E., Vitamaniuk, M., Doliba, N., Matschinsky, F., Barker, C. F., Naji, A. (2003) Insulin independence following isolated islet transplantation and single islet infusions Ann. Surg. 237,741-749[CrossRef][Medline]
    8. 8
  8. Kenmochi, T., Mullen, Y., Miyamoto, M., Stein, E. (1994) Protection of mouse islet isografts from early transplantation damage by nicotinamide treatment of recipients Transplant. Proc. 26,693[Medline]
    9. 9
  9. Bottino, R., Fernandez, L. A., Ricordi, C., Lehmann, R., Tsan, M. F., Oliver, R., Inverardi, L. (1998) Transplantation of allogeneic islets of Langerhans in the rat liver: effects of macrophage depletion on graft survival and microenvironment activation Diabetes 47,316-323[Abstract]
    10. 10
  10. Mandrup-Poulsen, T., Spinas, G. A., Prowse, S. J., Hansen, B. S., Jorgensen, D. W., Bendtzen, K., Nielsen, J. H., Nerup, J. (1987) Islet cytotoxicity of interleukin 1. Influence of culture conditions and islet donor characteristics Diabetes 36,641-647[Abstract]
    11. 11
  11. Nagata, M., Mullen, Y., Matsuo, S., Herrera, M., Clare-Salzler, M. (1990) Destruction of islet isografts by severe nonspecific inflammation Transplant. Proc. 22,855-856[Medline]
    12. 12
  12. Alejandro, R., Cutfield, R. G., Shienvold, F. L., Polonsky, K. S., Noel, J., Olson, L., Dillberger, J., Miller, J., Mintz, D. H. (1986) Natural history of intrahepatic canine islet cell autografts J. Clin. Invest. 78,1339-1348
    13. 13
  13. Biarnes, M., Montolio, M., Nacher, V., Raurell, M., Soler, J., Montanya, E. (2002) ß-cell death and mass in syngeneically transplanted islets exposed to short- and long-term hyperglycemia Diabetes 51,66-72[Abstract/Free Full Text]
    14. 14
  14. Kaufman, D. B., Platt, J. L., Rabe, F. L., Dunn, D. L., Bach, F. H., Sutherland, D. E. (1990) Differential roles of Mac-1+ cells, and CD4+ and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts J. Exp. Med. 172,291-302[Abstract/Free Full Text]
    15. 15
  15. Kaufman, D. B., Gores, P. F., Field, M. J., Farney, A. C., Gruber, S. A., Stephanian, E., Sutherland, D. E. (1994) Effect of 15-deoxyspergualin on immediate function and long-term survival of transplanted islets in murine recipients of a marginal islet mass Diabetes 43,778-783[Abstract]
    16. 16
  16. Tran, P. O., Gleason, C. E., Robertson, R. P. (2002) Inhibition of interleukin-1ß-induced COX-2 and EP3 gene expression by sodium salicylate enhances pancreatic islet ß-cell function Diabetes 51,1772-1778[Abstract/Free Full Text]
    17. 17
  17. Poggioli, R., Molano, R. D., Pileggi, A., Zahr, E., Ricordi, C., Inverardi, L. (2003) Selective inhibition of COX-2 results in improved islet graft function Am. J. Transplant. 3(Suppl. 5),208
    18. 18
  18. Mandrup-Poulsen, T. (2001) ß-cell apoptosis: stimuli and signaling Diabetes 50(Suppl. 1),S58-S63[Free Full Text]
    19. 19
  19. Paraskevas, S., Duguid, W. P., Maysinger, D., Feldman, L., Agapitos, D., Rosenberg, L. (1997) Apoptosis occurs in freshly isolated human islets under standard culture conditions Transplant. Proc. 29,750-752[CrossRef][Medline]
    20. 20
  20. Thomas, F. T., Hutchings, A., Contreras, J., Wu, J., Jiang, X. L., Eckhoff, D., Thomas, J. M. (2002) Islet transplantation in the twenty-first century Immunol. Res. 26,289-296[CrossRef][Medline]
    21. 21
  21. Mandrup-Poulsen, T. (1996) The role of interleukin-1 in the pathogenesis of IDDM Diabetologia 39,1005-1029[Medline]
    22. 22
  22. Montgomery, K. F., Osborn, L., Hession, C., Tizard, R., Goff, D., Vassallo, C., Tarr, P. I., Bomsztyk, K., Lobb, R., Harlan, J. M. (1991) Activation of endothelial-leukocyte adhesion molecule 1 (ELAM-1) gene transcription Proc. Natl. Acad. Sci. USA 88,6523-6527[Abstract/Free Full Text]
    23. 23
  23. Tran, P. O., Gleason, C. E., Poitout, V., Robertson, R. P. (1999) Prostaglandin E(2) mediates inhibition of insulin secretion by interleukin-1ß J. Biol. Chem. 274,31245-31248[Abstract/Free Full Text]
    24. 24
  24. Grilli, M., Chiu, J. J., Lenardo, M. J. (1993) NF-{kappa} B and Rel: participants in a multiform transcriptional regulatory system Int. Rev. Cytol. 143,1-62[Medline]
    25. 25
  25. Nathan, C. F. (1987) Secretory products of macrophages J. Clin. Invest. 79,319-326
    26. 26
  26. Bendtzen, K., Mandrup-Poulsen, T., Nerup, J., Nielsen, J. H., Dinarello, C. A., Svenson, M. (1986) Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans Science 232,1545-1547[Abstract/Free Full Text]
    27. 27
  27. Xenos, E. S., Stevens, R. B., Sutherland, D. E., Lokeh, A., Ansite, J. D., Casanova, D., Gores, P. F., Platt, J. L. (1994) The role of nitric oxide in IL-1 ß-mediated dysfunction of rodent islets of Langerhans. Implications for the function of intrahepatic islet grafts Transplantation 57,1208-1212[Medline]
    28. 28
  28. Corbett, J. A., Kwon, G., Marino, M. H., Rodi, C. P., Sullivan, P. M., Turk, J., McDaniel, M. L. (1996) Tyrosine kinase inhibitors prevent cytokine-induced expression of iNOS and COX-2 by human islets Am. J. Physiol. 270,C1581-C1587
    29. 29
  29. Eder, J. (1997) Tumour necrosis factor {alpha} and interleukin 1 signalling: do MAPKK kinases connect it all? Trends Pharmacol. Sci. 18,319-322[Medline]
    30. 30
  30. Cao, Z., Xiong, J., Takeuchi, M., Kurama, T., Goeddel, D. V. (1996) TRAF6 is a signal transducer for interleukin-1 Nature 383,443-446[CrossRef][Medline]
    31. 31
  31. Kwon, G., Corbett, J. A., Hauser, S., Hill, J. R., Turk, J., McDaniel, M. L. (1998) Evidence for involvement of the proteasome complex (26S) and NF{kappa}B in IL-1ß-induced nitric oxide and prostaglandin production by rat islets and RINm5F cells Diabetes 47,583-591[Abstract]
    32. 32
  32. Palombella, V. J., Rando, O. J., Goldberg, A. L., Maniatis, T. (1994) The ubiquitin-proteasome pathway is required for processing the NF-{kappa} B1 precursor protein and the activation of NF-{kappa} B Cell 78,773-785[CrossRef][Medline]
    33. 33
  33. Kopp, E., Ghosh, S. (1994) Inhibition of NF-{kappa} B by sodium salicylate and aspirin Science 265,956-959[Abstract/Free Full Text]
    34. 34
  34. Degitz, K., Li, L. J., Caughman, S. W. (1991) Cloning and characterization of the 5'-transcriptional regulatory region of the human intercellular adhesion molecule 1 gene J. Biol. Chem. 266,14024-14030[Abstract/Free Full Text]
    35. 35
  35. Wachlin, G., Augstein, P., Schroder, D., Kuttler, B., Kloting, I., Heinke, P., Schmidt, S. (2003) IL-1ß, IFN-{gamma} and TNF-{alpha} increase vulnerability of pancreatic ß cells to autoimmune destruction J. Autoimmun. 20,303-312[CrossRef][Medline]
    36. 36
  36. Xie, Q. W., Whisnant, R., Nathan, C. (1993) Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon {gamma} and bacterial lipopolysaccharide J. Exp. Med. 177,1779-1784[Abstract/Free Full Text]
    37. 37
  37. Leung, K., Betts, J. C., Xu, L., Nabel, G. J. (1994) The cytoplasmic domain of the interleukin-1 receptor is required for nuclear factor-{kappa} B signal transduction J. Biol. Chem. 269,1579-1582[Abstract/Free Full Text]
    38. 38
  38. Park, C., Kim, J. R., Shim, J. K., Kang, B. S., Park, Y. G., Nam, K. S., Lee, Y. C., Kim, C. H. (1999) Inhibitory effects of streptozotocin, tumor necrosis factor-{alpha}, and interleukin-1ß on glucokinase activity in pancreatic islets and gene expression of GLUT2 and glucokinase Arch. Biochem. Biophys. 362,217-224[CrossRef][Medline]
    39. 39
  39. Unger, R. H. (1991) Diabetic hyperglycemia: link to impaired glucose transport in pancreatic ß cells Science 251,1200-1205[Abstract/Free Full Text]
    40. 40
  40. Delaney, C. A., Pavlovic, D., Hoorens, A., Pipeleers, D. G., Eizirik, D. L. (1997) Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells Endocrinology 138,2610-2614[Abstract/Free Full Text]
    41. 41
  41. Yamamoto, H., Sugitani, A., Kitada, H., Arima, T., Nishiyama, K., Motoyama, K., Shiiba, M., Kawano, R., Morisaki, T., Nakafusa, Y., Tanaka, M. (2001) Effect of FR167653 on pancreatic ischemia-reperfusion injury in dogs Surgery 129,309-317[CrossRef][Medline]
    42. 42
  42. Cailleau, C., Diu-Hercend, A., Ruuth, E., Westwood, R., Carnaud, C. (1997) Treatment with neutralizing antibodies specific for IL-1ß prevents cyclophosphamide-induced diabetes in nonobese diabetic mice Diabetes 46,937-940[Abstract]
    43. 43
  43. Corbett, J. A., Sweetland, M. A., Wang, J. L., Lancaster, J. R., Jr, McDaniel, M. L. (1993) Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans Proc. Natl. Acad. Sci. USA 90,1731-1735[Abstract/Free Full Text]
    44. 44
  44. Eizirik, D. L., Sandler, S., Welsh, N., Cetkovic-Cvrlje, M., Nieman, A., Geller, D. A., Pipeleers, D. G., Bendtzen, K., Hellerstrom, C. (1994) Cytokines suppress human islet function irrespective of their effects on nitric oxide generation J. Clin. Invest. 93,1968-1974
    45. 45
  45. Sekine, N., Ishikawa, T., Okazaki, T., Hayashi, M., Wollheim, C. B., Fujita, T. (2000) Synergistic activation of NF-{kappa}ab and inducible isoform of nitric oxide synthase induction by interferon-{gamma} and tumor necrosis factor-{alpha} in INS-1 cells J. Cell. Physiol. 184,46-57[CrossRef][Medline]
    46. 46
  46. Chang, I., Kim, S., Kim, J. Y., Cho, N., Kim, Y. H., Kim, H. S., Lee, M. K., Kim, K. W., Lee, M. S. (2003) Nuclear factor {kappa}B protects pancreatic ß-cells from tumor necrosis factor-{alpha}-mediated apoptosis Diabetes 52,1169-1175[Abstract/Free Full Text]
    47. 47
  47. Stephens, L. A., Thomas, H. E., Ming, L., Grell, M., Darwiche, R., Volodin, L., Kay, T. W. (1999) Tumor necrosis factor-{alpha}-activated cell death pathways in NIT-1 insulinoma cells and primary pancreatic ß cells Endocrinology 140,3219-3227[Abstract/Free Full Text]
    48. 48
  48. Nussler, A. K., Carroll, P. B., Di Silvio, M., Rilo, H. L., Simmons, R. L., Starzl, T. E., Ricordi, C. (1992) Hepatic nitric oxide generation as a putative mechanism for failure of intrahepatic islet cell grafts Transplant. Proc. 24,2997[Medline]
    49. 49
  49. Palmer, J. P., Helqvist, S., Spinas, G. A., Molvig, J., Mandrup-Poulsen, T., Andersen, H. U., Nerup, J. (1989) Interaction of ß-cell activity and IL-1 concentration and exposure time in isolated rat islets of Langerhans Diabetes 38,1211-1216[Abstract]
    50. 50
  50. Corbett, J. A., McDaniel, M. L. (1995) Intraislet release of interleukin 1 inhibits ß cell function by inducing ß cell expression of inducible nitric oxide synthase J. Exp. Med. 181,559-568[Abstract/Free Full Text]
    51. 51
  51. Southern, C., Schulster, D., Green, I. C. (1990) Inhibition of insulin secretion by interleukin-1 ß and tumor necrosis factor-{alpha} via an L-arginine-dependent nitric oxide generating mechanism FEBS Lett. 276,42-44[CrossRef][Medline]
    52. 52
  52. Welsh, N., Eizirik, D. L., Bendtzen, K., Sandler, S. (1991) Interleukin-1 ß-induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase Endocrinology 129,3167-3173[Abstract/Free Full Text]
    53. 53
  53. Delaney, C. A., Green, M. H., Lowe, J. E., Green, I. C. (1993) Endogenous nitric oxide induced by interleukin-1 ß in rat islets of Langerhans and HIT-T15 cells causes significant DNA damage as measured by the ‘comet’ assay FEBS Lett. 333,291-295[CrossRef][Medline]
    54. 54
  54. Steller, H. (1995) Mechanisms and genes of cellular suicide Science 267,1445-1449[Abstract/Free Full Text]
    55. 55
  55. Xie, Q., Nathan, C. (1994) The high-output nitric oxide pathway: role and regulation J. Leukoc. Biol. 56,576-582[Abstract]
    56. 56
  56. Stevens, R. B., Lokeh, A., Ansite, J. D., Field, M. J., Gores, P. F., Sutherland, D. E. (1994) Role of nitric oxide in the pathogenesis of early pancreatic islet dysfunction during rat and human intraportal islet transplantation Transplant. Proc. 26,692[Medline]
    57. 57
  57. Herschman, H. R. (1996) Prostaglandin synthase 2 Biochim. Biophys. Acta 1299,125-140[Medline]
    58. 58
  58. Sorli, C. H., Zhang, H. J., Armstrong, M. B., Rajotte, R. V., Maclouf, J., Robertson, R. P. (1998) Basal expression of cyclooxygenase-2 and nuclear factor-interleukin 6 are dominant and coordinately regulated by interleukin 1 in the pancreatic islet Proc. Natl. Acad. Sci. USA 95,1788-1793[Abstract/Free Full Text]
    59. 59
  59. Xie, W., Merrill, J. R., Bradshaw, W. S., Simmons, D. L. (1993) Structural determination and promoter analysis of the chicken mitogen-inducible prostaglandin G/H synthase gene and genetic mapping of the murine homolog Arch. Biochem. Biophys. 300,247-252[CrossRef][Medline]
    60. 60
  60. Robertson, R. P., Chen, M. (1977) A role for prostaglandin E in defective insulin secretion and carbohydrate intolerance in diabetes mellitus J. Clin. Invest. 60,747-753
    61. 61
  61. Arakawa, T., Laneuville, O., Miller, C. A., Lakkides, K. M., Wingerd, B. A., DeWitt, D. L., Smith, W. L. (1996) Prostanoid receptors of murine NIH 3T3 and RAW 264.7 cells. Structure and expression of the murine prostaglandin EP4 receptor gene J. Biol. Chem. 271,29569-29575[Abstract/Free Full Text]
    62. 62
  62. Arita, S., Une, S., Ohtsuka, S., Kawahara, T., Kasraie, A., Smith, C. V., Mullen, Y. (2001) Increased islet viability by addition of beraprost sodium to collagenase solution Pancreas 23,62-67[CrossRef][Medline]
    63. 63
  63. Arita, S., Kasraie, A., Une, S., Ohtsuka, S., Kawahara, T., Smith, C. V., Mullen, Y. (1999) Improved recovery of cryopreserved canine islets by use of beraprost sodium Pancreas 19,289-296[Medline]
    64. 64
  64. Hearse, D. J., Manning, A. S., Downey, J. M., Yellon, D. M. (1986) Xanthine oxidase: a critical mediator of myocardial injury during ischemia and reperfusion? Acta Physiol. Scand. Suppl. 548,65-78[Medline]
    65. 65
  65. Southorn, P. A., Powis, G. (1988) Free radicals in medicine. I. Chemical nature and biologic reactions Mayo Clin. Proc. 63,381-389[Medline]
    66. 66
  66. Ar’Rajab, A., Dawidson, I. (1994) Ischemia-reperfusion injury in pancreas organ transplantation Zikria, B. A. Oz, M. O. eds. Reperfusion Injury and Clinical Capillary Leak Syndrome ,341-354 Futura Armonk, NY.
    67. 67
  67. Malaisse, W. J., Malaisse-Lagae, F., Sener, A., Pipeleers, D. G. (1982) Determinants of the selective toxicity of alloxan to the pancreatic B cell Proc. Natl. Acad. Sci. USA 79,927-930[Abstract/Free Full Text]
    68. 68
  68. Lenzen, S., Drinkgern, J., Tiedge, M. (1996) Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues Free Radic. Biol. Med. 20,463-466[CrossRef][Medline]
    69. 69
  69. Hotta, M., Tashiro, F., Ikegami, H., Niwa, H., Ogihara, T., Yodoi, J., Miyazaki, J. (1998) Pancreatic ß cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes J. Exp. Med. 188,1445-1451[Abstract/Free Full Text]
    70. 70
  70. Kubisch, H. M., Wang, J., Luche, R., Carlson, E., Bray, T. M., Epstein, C. J., Phillips, J. P. (1994) Transgenic copper/zinc superoxide dismutase modulates susceptibility to type I diabetes Proc. Natl. Acad. Sci. USA 91,9956-9959[Abstract/Free Full Text]
    71. 71
  71. Hohmeier, H. E., Thigpen, A., Tran, V. V., Davis, R., Newgard, C. B. (1998) Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1ß- induced cytotoxicity and reduces nitric oxide production J. Clin. Invest. 101,1811-1820[Medline]
    72. 72
  72. Benhamou, P. Y., Moriscot, C., Richard, M. J., Beatrix, O., Badet, L., Pattou, F., Kerr-Conte, J., Chroboczek, J., Lemarchand, P., Halimi, S. (1998) Adenovirus-mediated catalase gene transfer reduces oxidant stress in human, porcine and rat pancreatic islets Diabetologia 41,1093-1100[CrossRef][Medline]
    73. 73
  73. Winter, D. T., Eich, T., Jahr, H., Brendel, M. D., Bretzel, R. G. (2002) Influence of antioxidant therapy on islet graft survival Transplant. Proc. 34,2366-2368[CrossRef][Medline]
    74. 74
  74. Biozzi, G., Benacerraf, B., Halpern, B. (1953) Quantitative study of the granulopectic activity of the reticulo-endothelial system. II. A study of the kinetics of the R. E. S. in relation to the dose of carbon injected; relationship between the weight of the organs and their activity Br. J. Exp. Pathol. 34,441-457[Medline]
    75. 75
  75. Decker, K. (1990) Biologically active products of stimulated liver macrophages (Kupffer cells) Eur. J. Biochem. 192,245-261[Medline]
    76. 76
  76. Billiar, T. R., Curran, R. D., Stuehr, D. J., West, M. A., Bentz, B. G., Simmons, R. L. (1989) An L-arginine-dependent mechanism mediates Kupffer cell inhibition of hepatocyte protein synthesis in vitro J. Exp. Med. 169,1467-1472[Abstract/Free Full Text]
    77. 77
  77. Caldwell-Kenkel, J. C., Currin, R. T., Tanaka, Y., Thurman, R. G., Lemasters, J. J. (1991) Kupffer cell activation and endothelial cell damage after storage of rat livers: effects of reperfusion Hepatology 13,83-95[CrossRef][Medline]
    78. 78
  78. Clayton, H. A., Davies, J. E., Sutton, C. D., Bell, P. R., Dennison, A. R. (2001) A coculture model of intrahepatic islet transplantation: activation of Kupffer cells by islets and acinar tissue Cell Transplant. 10,101-108[Medline]
    79. 79
  79. Colletti, L. M., Remick, D. G., Burtch, G. D., Kunkel, S. L., Strieter, R. M., Campbell, D. A., Jr (1990) Role of tumor necrosis factor-{alpha} in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat J. Clin. Invest. 85,1936-1943
    80. 80
  80. Vargas, F., Vives-Pi, M., Somoza, N., Armengol, P., Alcalde, L., Marti, M., Costa, M., Serradell, L., Dominguez, O., Fernandez-Llamazares, J., Julian, J. F., Sanmarti, A., Pujol-Borrell, R. (1998) Endotoxin contamination may be responsible for the unexplained failure of human pancreatic islet transplantation Transplantation 65,722-727[CrossRef][Medline]
    81. 81
  81. Gray, D. W., Sutton, R., McShane, P., Peters, M., Morris, P. J. (1988) Exocrine contamination impairs implantation of pancreatic islets transplanted beneath the kidney capsule J. Surg. Res. 45,432-442[CrossRef][Medline]
    82. 82
  82. Kolb, H., Burkart, V., Appels, B., Hanenberg, H., Kantwerk-Funke, G., Kiesel, U., Funda, J., Schraermeyer, U., Kolb-Bachofen, V. (1990) Essential contribution of macrophages to islet cell destruction in vivo and in vitro J. Autoimmun. 3(Suppl. 1),117-120
    83. 83
  83. Schwizer, R. W., Leiter, E. H., Evans, R. (1984) Macrophage-mediated cytotoxicity against cultured pancreatic islet cells Transplantation 37,539-544[Medline]
    84. 84
  84. Heitmeier, M. R., Scarim, A. L., Corbett, J. A. (1997) Interferon-{gamma} increases the sensitivity of islets of Langerhans for inducible nitric-oxide synthase expression induced by interleukin 1 J. Biol. Chem. 272,13697-13704[Abstract/Free Full Text]
    85. 85
  85. Arnush, M., Heitmeier, M. R., Scarim, A. L., Marino, M. H., Manning, P. T., Corbett, J. A. (1998) IL-1 produced and released endogenously within human islets inhibits ß cell function J. Clin. Invest. 102,516-526[Medline]
    86. 86
  86. Heitmeier, M. R., Scarim, A. L., Corbett, J. A. (1999) Double-stranded RNA inhibits ß-cell function and induces islet damage by stimulating ß-cell production of nitric oxide J. Biol. Chem. 274,12531-12536[Abstract/Free Full Text]
    87. 87
  87. Lacy, P. E., Finke, E. H. (1991) Activation of intraislet lymphoid cells causes destruction of islet cells Am. J. Pathol. 138,1183-1190[Abstract]
    88. 88
  88. Lifson, N., Kramlinger, K. G., Mayrand, R. R., Lender, E. J. (1980) Blood flow to the rabbit pancreas with special reference to the islets of Langerhans Gastroenterology 79,466-473[Medline]
    89. 89
  89. Jansson, L., Hellerstrom, C. (1983) Stimulation by glucose of the blood flow to the pancreatic islets of the rat Diabetologia 25,45-50[Medline]
    90. 90
  90. Stagner, J. I., Mokshagundam, S., Samols, E. (1995) Hormone secretion from transplanted islets is dependent upon changes in islet revascularization and islet architecture Transplant. Proc. 27,3251-3254[Medline]
    91. 91
  91. Walsh, T. J., Eggleston, J. C., Cameron, J. L. (1982) Portal hypertension, hepatic infarction, and liver failure complicating pancreatic islet autotransplantation Surgery 91,485-487[Medline]
    92. 92
  92. Griffith, R. C., Scharp, D. W., Hartman, B. K., Ballinger, W. F., Lacy, P. E. (1977) A morphologic study of intrahepatic portal-vein islet isografts Diabetes 26,201-214[Abstract]
    93. 93
  93. Stagner, J. I., Samols, E. (1990) The induction of capillary bed development by endothelial cell growth factor before islet transplantation may prevent islet ischemia Transplant. Proc. 22,824-828[Medline]
    94. 94
  94. Parr, E. L., Bowen, K. M., Lafferty, K. J. (1980) Cellular changes in cultured mouse thyroid glands and islets of Langerhans Transplantation 30,135-141[Medline]
    95. 95
  95. Vasir, B., Aiello, L. P., Yoon, K. H., Quickel, R. R., Bonner-Weir, S., Weir, G. C. (1998) Hypoxia induces vascular endothelial growth factor gene and protein expression in cultured rat islet cells Diabetes 47,1894-1903[Abstract]
    96. 96
  96. Vajkoczy, P., Olofsson, A. M., Lehr, H. A., Leiderer, R., Hammersen, F., Arfors, K. E., Menger, M. D. (1995) Histogenesis and ultrastructure of pancreatic islet graft microvasculature. Evidence for graft revascularization by endothelial cells of host origin Am. J. Pathol. 146,1397-1405[Abstract]
    97. 97
  97. Vajkoczy, P., Menger, M. D., Simpson, E., Messmer, K. (1995) Angiogenesis and vascularization of murine pancreatic islet isografts Transplantation 60,123-127[Medline]
    98. 98
  98. Merchant, F. A., Diller, K. R., Aggarwal, S. J., Bovik, A. C. (1997) Angiogenesis in cultured and cryopreserved pancreatic islet grafts Transplantation 63,1652-1660[CrossRef][Medline]
    99. 99
  99. Sezai, S., Sakurabayashi, S., Yamamoto, Y., Morita, T., Hirano, M., Oka, H. (1993) Hepatic arterial and portal venous oxygen content and extraction in liver cirrhosis Liver 13,31-35[Medline]
    100. 100
  100. Carlsson, P. O., Liss, P., Andersson, A., Jansson, L. (1998) Measurements of oxygen tension in native and transplanted rat pancreatic islets Diabetes 47,1027-1032[Abstract]
    101. 101
  101. Carlsson, P. O., Palm, F., Andersson, A., Liss, P. (2001) Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site Diabetes 50,489-495[Abstract/Free Full Text]
    102. 102
  102. Carlsson, P. O., Palm, F. (2002) Oxygen tension in isolated transplanted rat islets and in islets of rat whole-pancreas transplants Transpl. Int. 15,581-585[CrossRef][Medline]
    103. 103
  103. Carlsson, P. O., Palm, F., Andersson, A., Liss, P. (2000) Chronically decreased oxygen tension in rat pancreatic islets transplanted under the kidney capsule Transplantation 69,761-766[CrossRef][Medline]
    104. 104
  104. Dionne, K. E., Colton, C. K., Yarmush, M. L. (1993) Effect of hypoxia on insulin secretion by isolated rat and canine islets of Langerhans Diabetes 42,12-21[Abstract]
    105. 105
  105. Davalli, A. M., Scaglia, L., Zangen, D. H., Hollister, J., Bonner-Weir, S., Weir, G. C. (1996) Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function Diabetes 45,1161-1167[Abstract]
    106. 106
  106. Han, D. J., Kim, S. C., Wee, Y. M. (2003) Central cell death in isolated pancreatic islets is inherent to their spherical structure Transplantation 76(Suppl. 4),S67-S68
    107. 107
  107. Juang, J. H., Hsu, B. R., Kuo, C. H., Uengt, S. W. (2002) Beneficial effects of hyperbaric oxygen therapy on islet transplantation Cell Transplant. 11,95-101[Medline]
    108. 108
  108. Parks, D. A., Granger, D. N. (1986) Contributions of ischemia and reperfusion to mucosal lesion formation Am. J. Physiol. 250,G749-G753
    109. 109
  109. Korthuis, R. J., Smith, J. K., Carden, D. L. (1989) Hypoxic reperfusion attenuates postischemic microvascular injury Am. J. Physiol. 256,H315-H319
    110. 110
  110. Thurman, R. G., Marzi, I., Seitz, G., Thies, J., Lemasters, J. J., Zimmerman, F. (1988) Hepatic reperfusion injury following orthotopic liver transplantation in the rat Transplantation 46,502-506[Medline]
    111. 111
  111. Carden, D. L., Granger, D. N. (2000) Pathophysiology of ischaemia-reperfusion injury J. Pathol. 190,255-266[CrossRef][Medline]
    112. 112
  112. Adams, D. H., Hubscher, S. G., Shaw, J., Rothlein, R., Neuberger, J. M. (1989) Intercellular adhesion molecule 1 on liver allografts during rejection Lancet 2,1122-1125[Medline]
    113. 113
  113. Ichikawa, H., Flores, S., Kvietys, P. R., Wolf, R. E., Yoshikawa, T., Granger, D. N., Aw, T. Y. (1997) Molecular mechanisms of anoxia/reoxygenation-induced neutrophil adherence to cultured endothelial cells Circ. Res. 81,922-931[Abstract/Free Full Text]
    114. 114
  114. Arai, K., Sunamura, M., Wada, Y., Takahashi, M., Kobari, M., Kato, K., Yagita, H., Okumura, K., Matsuno, S. (1999) Preventing effect of anti-ICAM-1 and anti-LFA-1 monoclonal antibodies on murine islet allograft rejection Int. J. Pancreatol. 26,23-31[Medline]
    115. 115
  115. Katz, S. M., Bennett, F., Stecker, K., Clark, J. H., Pham, T., Wang, M. E., Kahan, B. D., Stepkowski, S. M. (2000) ICAM-1 antisense oligodeoxynucleotide improves islet allograft survival and function Cell Transplant. 9,817-828[Medline]
    116. 116
  116. Augstein, P., Dunger, A., Heinke, P., Wachlin, G., Berg, S., Hehmke, B., Salzsieder, E. (2003) Prevention of autoimmune diabetes in NOD mice by troglitazone is associated with modulation of ICAM-1 expression on pancreatic islet cells and IFN-{gamma} expression in splenic T cells Biochem. Biophys. Res. Commun. 304,378-384[CrossRef][Medline]
    117. 117
  117. Chakrabarti, D., Huang, X., Beck, J., Henrich, J., McFarland, N., James, R. F., Stewart, T. A. (1996) Control of islet intercellular adhesion molecule-1 expression by interferon-{alpha} and hypoxia Diabetes 45,1336-1343[Abstract]
    118. 118
  118. Piemonti, L., Leone, B. E., Nano, R., Saccani, A., Monti, P., Maffi, P., Bianchi, G., Sica, A., Peri, G., Melzi, R., Aldrighetti, L., Secchi, A., Di Carlo, V., Allavena, P., Bertuzzi, F. (2002) Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation Diabetes 51,55-65[Abstract/Free Full Text]
    119. 119
  119. Baker, M. S., Chen, X., Rotramel, A., Nelson, J., Kaufman, D. B. (2003) Proinflammatory cytokines induce NF-{kappa}B-dependent/NO-independent chemokine gene expression in MIN6 ß cells J. Surg. Res. 110,295-303[CrossRef][Medline]
    120. 120
  120. Hanahan, D. J. (1986) Platelet activating factor: a biologically active phosphoglyceride Annu. Rev. Biochem. 55,483-509[CrossRef][Medline]
    121. 121
  121. Carlsen, E., Flatmark, A., Prydz, H. (1988) Cytokine-induced procoagulant activity in monocytes and endothelial cells. Further enhancement by cyclosporine Transplantation 46,575-580[Medline]
    122. 122
  122. Ogawa, S., Gerlach, H., Esposito, C., Pasagian-Macaulay, A., Brett, J., Stern, D. (1990) Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium. Increased monolayer permeability and induction of procoagulant properties J. Clin. Invest. 85,1090-1098
    123. 123
  123. Yoshimura, N., Kobayashi, Y., Nakamura, K., Yoshimura, R., Yamagishi, H., Oka, T. (1998) Role of tissue factor in ischemic reperfusion injury: iv). The effect of tissue factor pathway inhibitor on the survival rate in vivo Transplant. Proc. 30,2300-2301[CrossRef][Medline]
    124. 124
  124. Morrissey, J. H. (2004) Tissue factor: a key molecule in hemostatic and nonhemostatic systems Int. J. Hematol. 79,103-108[Medline]
    125. 125
  125. Nawroth, P. P., Stern, D. M. (1986) Modulation of endothelial cell hemostatic properties by tumor necrosis factor J. Exp. Med. 163,740-745[Abstract/Free Full Text]
    126. 126
  126. Moberg, L., Johansson, H., Lukinius, A., Berne, C., Foss, A., Kallen, R., Ostraat, O., Salmela, K., Tibell, A., Tufveson, G., Elgue, G., Nilsson, E. K., Korsgren, O., Nilsson, B. (2002) Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation Lancet 360,2039-2045[CrossRef][Medline]
    127. 127
  127. Sever, C. E., Demetris, A. J., Zeng, Y., Tzakis, A., Fung, J. J., Starzl, T. E., Ricordi, C. (1992) Islet cell allotransplantation in diabetic patients. Histologic findings in four adults simultaneously receiving kidney or liver transplants Am. J. Pathol. 140,1255-1260[Abstract]
    128. 128
  128. Arai, M., Mochida, S., Ohno, A., Fujiwara, K. (1996) Blood coagulation in the hepatic sinusoids as a contributing factor in liver injury following orthotopic liver transplantation in the rat Transplantation 62,1398-1401[CrossRef][Medline]
    129. 129
  129. Cywes, R., Packham, M. A., Tietze, L., Sanabria, J. R., Harvey, P. R., Phillips, M. J., Strasberg, S. M. (1993) Role of platelets in hepatic allograft preservation injury in the rat Hepatology 18,635-647[CrossRef][Medline]
    130. 130
  130. Bennet, W., Sundberg, B., Groth, C. G., Brendel, M. D., Brandhorst, D., Brandhorst, H., Bretzel, R. G., Elgue, G., Larsson, R., Nilsson, B., Korsgren, O. (1999) Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes 48,1907-1914[Abstract]
    131. 131
  131. Ozmen, L., Ekdahl, K. N., Elgue, G., Larsson, R., Korsgren, O., Nilsson, B. (2002) 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 51,1779-1784[Abstract/Free Full Text]
    132. 132
  132. Starzl, T. E., Francavilla, A., Halgrimson, C. G., Francavilla, F. R., Porter, K. A., Brown, T. H., Putnam, C. W. (1973) The origin, hormonal nature, and action of hepatotrophic substances in portal venous blood Surg. Gynecol. Obstet. 137,179-199[Medline]
    133. 133
  133. Hirshberg, B., Mog, S., Patterson, N., Leconte, J., Harlan, D. M. (2002) Histopathological study of intrahepatic islets transplanted in the nonhuman primate model using Edmonton protocol immunosuppression J. Clin. Endocrinol. Metab. 87,5424-5429[Abstract/Free Full Text]
    134. 134
  134. Ryan, E. A., Lakey, J. R., Rajotte, R. V., Korbutt, G. S., Kin, T., Imes, S., Rabinovitch, A., Elliott, J. F., Bigam, D., Kneteman, N. M., Warnock, G. L., Larsen, I., Shapiro, A. M. (2001) Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol Diabetes 50,710-719[Abstract/Free Full Text]
    135. 135
  135. Curran, R. D., Billiar, T. R., Stuehr, D. J., Hofmann, K., Simmons, R. L. (1989) Hepatocytes produce nitrogen oxides from L-arginine in response to inflammatory products of Kupffer cells J. Exp. Med. 170,1769-1774[Abstract/Free Full Text]
    136. 136
  136. Tenhunen, R., Marver, H. S., Schmid, R. (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase Proc. Natl. Acad. Sci. USA 61,748-755[Free Full Text]
    137. 137
  137. Rizzardini, M., Terao, M., Falciani, F., Cantoni, L. (1993) Cytokine induction of haem oxygenase mRNA in mouse liver. Interleukin 1 transcriptionally activates the haem oxygenase gene Biochem. J. 290,343-347
    138. 138
  138. Durante, W., Kroll, M. H., Christodoulides, N., Peyton, K. J., Schafer, A. I. (1997) Nitric oxide induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle cells Circ. Res. 80,557-564[Abstract/Free Full Text]
    139. 139
  139. Tobiasch, E., Gunther, L., Bach, F. H. (2001) Heme oxygenase-1 protects pancreatic ß cells from apoptosis caused by various stimuli J. Investig. Med. 49,566-571[Medline]
    140. 140
  140. Ye, J., Laychock, S. G. (1998) A protective role for heme oxygenase expression in pancreatic islets exposed to interleukin-1ß Endocrinology 139,4155-4163[Abstract/Free Full Text]
    141. 141
  141. Pileggi, A., Molano, R. D., Berney, T., Cattan, P., Vizzardelli, C., Oliver, R., Fraker, C., Ricordi, C., Pastori, R. L., Bach, F. H., Inverardi, L. (2001) Heme oxygenase-1 induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation Diabetes 50,1983-1991[Abstract/Free Full Text]
    142. 142
  142. Ribeiro, M. M., Klein, D., Pileggi, A., Molano, R. D., Fraker, C., Ricordi, C., Inverardi, L., Pastori, R. L. (2003) Heme oxygenase-1 fused to a TAT peptide transduces and protects pancreatic ß-cells Biochem. Biophys. Res. Commun. 305,876-881[CrossRef][Medline]
    143. 143
  143. Stocker, R., Yamamoto, Y., McDonagh, A. F., Glazer, A. N., Ames, B. N. (1987) Bilirubin is an antioxidant of possible physiological importance Science 235,1043-1046[Abstract/Free Full Text]
    144. 144
  144. Gunther, L., Berberat, P. O., Haga, M., Brouard, S., Smith, R. N., Soares, M. P., Bach, F. H., Tobiasch, E. (2002) Carbon monoxide protects pancreatic ß-cells from apoptosis and improves islet function/survival after transplantation Diabetes 51,994-999[Abstract/Free Full Text]
    145. 145
  145. Otterbein, L. E., Bach, F. H., Alam, J., Soares, M., Tao, L. H., Wysk, M., Davis, R. J., Flavell, R. A., Choi, A. M. (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway Nat. Med. 6,422-428[CrossRef][Medline]
    146. 146
  146. Balasa, B., Van Gunst, K., Jung, N., Katz, J. D., Sarvetnick, N. (2000) IL-10 deficiency does not inhibit insulitis and accelerates cyclophosphamide-induced diabetes in the nonobese diabetic mouse Cell. Immunol. 202,97-102[CrossRef][Medline]
    147. 147
  147. Pennline, K. J., Roque-Gaffney, E., Monahan, M. (1994) Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse Clin. Immunol. Immunopathol. 71,169-175[CrossRef][Medline]
    148. 148
  148. Zhang, Y. C., Pileggi, A., Agarwal, A., Molano, R. D., Powers, M., Brusko, T., Wasserfall, C., Goudy, K., Zahr, E., Poggioli, R., Scott-Jorgensen, M., Campbell-Thompson, M., Crawford, J. M., Nick, H., Flotte, T., Ellis, T. M., Ricordi, C., Inverardi, L., Atkinson, M. A. (2003) Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice Diabetes 52,708-716[Abstract/Free Full Text]
    149. 149
  149. Smith, D. K., Korbutt, G. S., Suarez-Pinzon, W. L., Kao, D., Rajotte, R. V., Elliott, J. F. (1997) Interleukin-4 or interleukin-10 expressed from adenovirus-transduced syngeneic islet grafts fails to prevent ß cell destruction in diabetic NOD mice Transplantation 64,1040-1049[Medline]



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