Effect of tumor necrosis factor α and intercellular adhesion molecule-1 expression on immunogenicity of murine liver cells in mice

Bumgardner, Ginny L.; Li, Jiashun; Apte, Sach; Heininger, Marie; Frankel, Wendy L.

doi:10.1002/hep.510280226

Cited by 18 publications

(16 citation statements)

References 34 publications

(39 reference statements)

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“…Why CD18-positive neutrophils would kill hepatocytes but not biliary cells after ANIT treatment is uncertain. Hepatocytes and biliary cells upregulate ICAM-1 expression in response to injury (6,8,28,50), and thus both are potential targets of CD18-mediated cytotoxicity (2). It is possible that ICAM-1 is upregulated more strongly on hepatocytes than biliary cells after ANIT treatment.…”

Section: Discussionmentioning

confidence: 99%

ANIT toxicity toward mouse hepatocytes in vivo is mediated primarily by neutrophils via CD18

Kodali¹,

Wu²,

Lahiji³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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. ANIT toxicity toward mouse hepatocytes in vivo is mediated primarily by neutrophils via CD18. Am J Physiol Gastrointest Liver Physiol 291: G355-G363, 2006. First published April 13, 2006 doi:10.1152/ajpgi.00458.2005.-␣-Naphthylisothiocyanate (ANIT) is a hepatotoxicant that causes acute cholestatic hepatitis with infiltration of neutrophils around bile ducts and necrotic hepatocytes. The objective of this study was to determine whether the ␤2-integrin CD18, which plays an important role in leukocyte invasion and cytotoxicity, contributes to ANIT-induced hepatic inflammation and liver injury. Mice with varying levels of leukocyte CD18 expression were treated with ANIT and monitored for hepatic neutrophil influx and liver injury over 48 h. Mice that were partially deficient in CD18 (30% of normal levels) developed periportal inflammation and widespread hepatic necrosis after ANIT treatment in a pattern identical to that in wild-type (WT) mice. In contrast, mice that completely lack CD18 (CD18 null) were resistant to ANIT toxicity. Forty-eight hours after ANIT, CD18-null mice displayed 60% lower serum alanine aminotransferase (ALT) levels and 75% less hepatic necrosis, as shown by morphometry, than WT mice. This was true despite evidence that ANIT still provoked hepatic neutrophil influx in CD18-null mice. WT mice could also be protected from ANIT-induced hepatocellular necrosis, by depleting the animals of neutrophils. Notably, neither CD18-null mice nor neutrophil-depleted WT mice exhibited any attenuation of bile duct injury or cholestasis due to ANIT. We conclude from these experiments that neutrophils invade ANIT-treated livers in a CD18-independent fashion but utilize CD18 to induce hepatocellular cytotoxicity. The results emphasize that neutrophil-mediated amplification of ANIT-induced liver injury is directed toward hepatocytes rather than cholangiocytes. In fact, the data indicate that the majority of ANIT toxicity toward hepatocytes in vivo is neutrophil driven.

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Section: Discussionmentioning

confidence: 99%

ANIT toxicity toward mouse hepatocytes in vivo is mediated primarily by neutrophils via CD18

Kodali¹,

Wu²,

Lahiji³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…We have previously noted that hepatocytes constitutively express ICAM-1 which is up-regulated by the inflammatory cytokine TNF-a. Therefore, treatment with anti-LFA-1 mAb may influence direct T-cell interaction with donor hepatocytes (42).…”

Section: Discussionmentioning

confidence: 99%

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

Wang

Gao

Lunsford

et al. 2003

American Journal of Transplantation

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Allogeneic hepatocytes elicit CD4-dependent and (CD4-independent) CD8 + T-cell-initiated graft rejection. The (CD4-independent) CD8 + T-cell pathway is resistant to immunosuppressive strategies that readily and indefinitely suppress CD4 + T-cell-dependent rejection responses. Consequently, successful immunoregulation of hepatocyte-initiated immune responses requires a strategy which regulates both CD4-dependent and CD8-dependent rejection responses. Interference with CD40/CD40 ligand (CD40L) costimulation only transiently suppresses CD4-and CD8-dependent hepatocyte rejection. Interference with CD28/B7 costimulation transiently suppresses CD4-dependent hepatocyte rejection, but is ineffective for suppression of CD8-dependent hepatocyte rejection. To date, hepatocyte survival > 60 days post-transplant has not been achieved by any immunotherapeutic strategy. In the current study, we evaluated a novel immunosuppressive strategy which targets both LFA-1 and CD40L-mediated signals. Targeting LFA-1 suppressed (CD4-independent) CD8 + T-cell-initiated hepatocyte rejection such that allogeneic hepatocyte survival > 60 days was achieved in 70% of CD4 KO mice. Targeting both LFA-1-mediated signals and CD40/CD40L costimulation resulted in synergistic effects, such that hepatocellular survival > 60 days was achieved in 100% of C57BL/6 mice (which have both CD4-and CD8-dependent T-cell pathways available).

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“…Responder splenocytes were prepared by mechanical disruption of the spleens from euthanized naïve CD4 KO mice or CD4 KO mice primed by transplantation of islets or hepatocytes, as previously described (25). Proliferation of responder splenocytes in mixed lymphocyte reaction (MLR) was determined by quantifying reduction of the fluorogenic indicator Alamar Blue (Biosource, Camarillo, CA, USA) (26).…”

Section: In Vitro Mixed Lymphocyte Reactionmentioning

confidence: 99%

Activation and Maturation of Alloreactive CD4-Independent, CD8+ Cytolytic T Cells

Lunsford

Horne

Koester

et al. 2006

American Journal of Transplantation

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The goal of this study was to determine the in vivo conditions that promote activation of the (CD4-independent) CD8 + T cell-mediated rejection pathway. We have previously noted that hepatocellular but not islet allografts readily activate this rejection pathway. In the current study, we utilized these two cell transplant models to investigate whether differences in host cell recruitment to the graft site, expression of T-cell activation markers by CD8 + graft infiltrating cells (GICs), and/or development of delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte cell-mediated effector functions could account for the differential transplant outcomes. The collective results demonstrate that recruitment of CD8 + T cells to the site of transplant, CD103 or CD69 expression on CD8+ GICs, and activation of alloreactive DTH responses are insufficient to initiate CD4-independent, CD8-dependent transplant rejection. Instead, rejection by alloreactive (CD4-independent) CD8 + T cells correlated with expression of CD25, CD154 and CD43 by CD8 + GICs, in vitro alloproliferation by recipient CD8 + T cells, and the development of in vivo allospecific cytolytic effector function. These results suggest that tissue-derived factors influence the activation and maturation of (CD4-independent) CD8 + T cells into cytolytic effectors, which correlates with transplant rejection.

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Effect of tumor necrosis factor α and intercellular adhesion molecule-1 expression on immunogenicity of murine liver cells in mice

Cited by 18 publications

References 34 publications

ANIT toxicity toward mouse hepatocytes in vivo is mediated primarily by neutrophils via CD18

ANIT toxicity toward mouse hepatocytes in vivo is mediated primarily by neutrophils via CD18

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

Activation and Maturation of Alloreactive CD4-Independent, CD8+ Cytolytic T Cells

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