Immunogenic role of kupffer cells in a rat model of acute liver allograft rejection

Imamura, Hiroshi; Laberge, Sophie; Brault, Antoine; Côté, Jean; Huet, Pierre‐Michel

doi:10.1002/lt.500010610

Cited by 3 publications

(4 citation statements)

References 20 publications

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“…These data imply that the primary role of liver APCs in the development of GVHD may be as a cellular magnet, attracting activated allogeneic T cells specific for host tissue Ags. Although there is still a controversy as to whether hepatic APCs might themselves be capable of inducing the allo-specific responses (39,40), it is clear that activated Kupffer cells can produce high levels of IL-6, TNF-␣ (41)(42)(43)(44)(45)(46), and chemokines such as MIP1␣ (15). Thus, hepatic macrophages could direct the trafficking of activated allogeneic CD8 ϩ T cells into the liver by the means of the chemokines secreted either by hepatic macrophages themselves or by other cells in the liver via the proinflammatory stimulation of macrophage-derived IL-6 and TNF-␣, leading to hepatic GVHD.…”

Section: Cd8mentioning

confidence: 99%

APCs in the Liver and Spleen Recruit Activated Allogeneic CD8+ T Cells to Elicit Hepatic Graft-Versus-Host Disease

Zhang

Shlomchik

Joe

et al. 2002

The Journal of Immunology

131

108

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Host APCs are required for initiating T cell-dependent acute graft-vs-host disease (GVHD), but the role of APCs in the effector phase of acute GVHD is not known. To measure the effect of tissue-resident APCs on the local development of acute GVHD, we selectively depleted host macrophages and DCs from the livers and spleens, but not from the skin, peripheral lymph nodes (PLN), or mesenteric lymph nodes (MLN), of C57BL/6 (B6) mice by i.v. administration of liposomal clodronate before allogeneic bone marrow transplantation. Depletion of host hepatic and splenic macrophages and DCs significantly inhibited the proliferation of donor C3H.SW CD8+ T cells in the spleen, but not in the PLN or MLN, of B6 mice. Such organ-selective depletion of host tissue APCs also markedly reduced the trafficking of allogeneic CD8+ T cells into the livers and spleens, but not PLN and MLN, of B6 recipients compared with that of the control mice. Acute hepatic, but not cutaneous, GVHD was inhibited as well, resulting in improved survival of liposomal clodronate-treated B6 recipients. When C3H.SW CD8+ T cells were activated in normal B6 recipients, recovered, and adoptively transferred into secondary B6 recipients, activated donor CD8+ T cells rapidly migrated into the livers and spleens of control B6 recipients but were markedly decreased in B6 mice that were depleted of hepatic and splenic macrophages and DCs. Thus, tissue-resident APCs control the local recruitment of allo-reactive donor T cells and the subsequent development of acute GVHD.

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Section: Cd8mentioning

confidence: 99%

APCs in the Liver and Spleen Recruit Activated Allogeneic CD8+ T Cells to Elicit Hepatic Graft-Versus-Host Disease

Zhang

Shlomchik

Joe

et al. 2002

The Journal of Immunology

131

108

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“…Macrophages reside in every solid organ . Tissue-resident macrophages are likely derived from circulating monocytes , and are functionally diverse, playing important roles in tissue homeostasis, repair, and response to foreign pathogens. Macrophages tend to adapt to their tissue location, and their biological function is related to their location within the tissue architecture.…”

mentioning

confidence: 99%

Phenotype Determines Nanoparticle Uptake by Human Macrophages from Liver and Blood

et al. 2017

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A significant challenge to delivering therapeutic doses of nanoparticles to targeted disease sites is the fact that most nanoparticles become trapped in the liver. Liver-resident macrophages, or Kupffer cells, are key cells in the hepatic sequestration of nanoparticles. However, the precise role that the macrophage phenotype plays in nanoparticle uptake is unknown. Here, we show that the human macrophage phenotype modulates hard nanoparticle uptake. Using gold nanoparticles, we examined uptake by human monocyte-derived macrophages that had been driven to a "regulatory" M2 phenotype or an "inflammatory" M1 phenotype and found that M2-type macrophages preferentially take up nanoparticles, with a clear hierarchy among the subtypes (M2c > M2 > M2a > M2b > M1). We also found that stimuli such as LPS/IFN-γ rather than with more "regulatory" stimuli such as TGF-β/IL-10 reduce per cell macrophage nanoparticle uptake by an average of 40%. Primary human Kupffer cells were found to display heterogeneous expression of M1 and M2 markers, and Kupffer cells expressing higher levels of M2 markers (CD163) take up significantly more nanoparticles than Kupffer cells expressing lower levels of surface CD163. Our results demonstrate that hepatic inflammatory microenvironments should be considered when studying liver sequestration of nanoparticles, and that modifying the hepatic microenvironment might offer a tool for enhancing or decreasing this sequestration. Our findings also suggest that models examining the nanoparticle/macrophage interaction should include studies with primary tissue macrophages.

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“…13,31,32 Conversely, others failed to show an effect of Kupffer cell blockade on hepatocyte damage during preservation, 24 on functions of hepatocytes 20,21,34 and sinusoidal endothelial cells 20,34 during reperfusion, or on graft survival. 34,35 In addition, conflicting results were obtained by the same laboratory 21,36 and even within the same study. 16 For example, although leukocytes were found to adhere to the sinusoidal wall by a Kupffer cell-dependent mechanism after short preservation periods (which had no effect on graft injury), leukocyte adherence and liver damage after long preservation times were independent of the presence or absence of Kupffer cells.…”

Section: Is Deterioration Of Liver Microcirculation Exclusively Respomentioning

confidence: 78%

“…For example, when warm ischemia preceded preservation, 30 or when Kupffer cells were primed by donor 36 or recipient endotoxemia, 29 or liver microcirculation was impaired by induction of a fatty liver 31 or graft manipulation before harvest, 32 Kupffer cells markedly influenced hepatocyte injury and graft function. Conversely, when Kupffer cells were primed by preservation only, their effects on graft injury were absent 20,21,24,34,35 or minimal from the clinical point of view (i.e., increasing survival from 12 to 40 hours). 13 Therefore, it seems more logical to accept the hypothesis that Kupffer cells may critically contribute to graft injury in certain specific clinical situations (e.g., endotoxemia, impaired microcirculation in fatty livers), whereas in other situations, the effect of Kupffer cells on graft viability may be less important.…”

Section: Is Deterioration Of Liver Microcirculation Exclusively Respomentioning

confidence: 99%

Role of hepatocytes and bile duct cells in preservation-reperfusion injury of liver grafts

Kukan

Haddad

2001

Liver Transplantation

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In liver transplantation, it is currently hypothesized that nonparenchymal cell damage and/or activation is the major cause of preservation-related graft injury. Because parenchymal cells (hepatocytes) appear morphologically well preserved even after extended cold preservation, their injury after warm reperfusion is ascribed to the consequences of nonparenchymal cell damage and/or activation. However, accumulating evidence over the past decade indicated that the current hypothesis cannot fully explain preservation-related liver graft injury. We review data obtained in animal and human liver transplantation and isolated perfused animal livers, as well as isolated cell models to highlight growing evidence of the importance of hepatocyte disturbances in the pathogenesis of normal and fatty graft injury. Particular attention is given to preservation time-dependent decreases in high-energy adenine nucleotide levels in liver cells, a circumstance that (1) sensitizes hepatocytes to various stimuli and insults, (2) correlates well with graft function after liver transplantation, and (3) may also underlie the preservation timedependent increase in endothelial cell damage. We also review damage to bile duct cells, which is increasingly being recognized as important in the long-lasting phase of reperfusion injury. The role of hydrophobic bile salts in that context is particularly assessed. Finally, a number of avenues aimed at preserving hepatocyte and bile duct cell integrity are discussed in the context of liver transplantation therapy as a complement to reducing nonparenchymal cell damage and/or activation. (Liver Transpl 2001;7: 381-400.)A lthough the use of University of Wisconsin (UW) solution has permitted an increase in mean preservation time, the incidence of graft dysfunction still persists, 1,2 contributing significantly to a more than 20% per year mortality rate for patients in liver transplantation centers in the United States. 3 In addition, when storage time exceeds 10 to 12 hours, such late posttransplantation complications as biliary strictures occur in more than 25% of liver transplant recipients. [4][5][6] To prevent or minimize graft dysfunction and posttransplantation complications, it is essential to fully understand the importance of individual liver cell types in graft injury induced by cold storage and reperfusion. Insight into the cellular and molecular basis of these injuries will lead to the development of better intervention strategies, which is very important because graft dysfunction results in increased morbidity and enhances mortality rates. 7,8 Moreover, up to 30% of patients with graft dysfunction need retransplantation as early as within the first 3 months after transplantation, 2,7,8 which increases the demand on an already short pool of donor organs.According to morphological studies, cold preservation leads to injuries of nonparenchymal cells, whereas liver parenchymal cells appear well preserved. It is currently hypothesized that sinusoidal endothelial cell impairment, 9-11 activatio...

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Immunogenic role of kupffer cells in a rat model of acute liver allograft rejection

Cited by 3 publications

References 20 publications

APCs in the Liver and Spleen Recruit Activated Allogeneic CD8+ T Cells to Elicit Hepatic Graft-Versus-Host Disease

APCs in the Liver and Spleen Recruit Activated Allogeneic CD8+ T Cells to Elicit Hepatic Graft-Versus-Host Disease

Phenotype Determines Nanoparticle Uptake by Human Macrophages from Liver and Blood

Role of hepatocytes and bile duct cells in preservation-reperfusion injury of liver grafts

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