CD40L (CD154) expression in human liver allografts during chronic ductopenic rejection

Abstract

The CD40-CD40L (CD154) interaction plays a pivotal role in the effector mechanisms of allograft rejection. Blockade of the CD40/CD40L costimulatory pathway prevents the development of chronic allograft rejection in several animal transplant models. The relevance of in situ CD40 and CD40L expression in human liver allografts was assessed by immunohistochemistry during ductopenic chronic rejection (CR). In CR allograft specimens (n ‫؍‬ 8), marked CD40L expression was detected on Kupffer cells (KCs) and sinusoidal macrophages with a unique centrilobular distribution (P F .001). The CD40L؉ KCs and macrophages were shown to be CD68؉ after immunohistochemical analysis of serial sections with anti-CD68 monoclonal antibody. Moderate staining of vascular and sinusoidal endothelial cells and mononuclear infiltrates was observed in some CR cases. These findings were in contrast to the absence of CD40L expression in controls (n ‫؍‬ 11) consisting of stable liver allograft and normal liver tissue specimens. Only occasional CD40 expression in some cases of CR and controls was observed. In CR, CD40L (CD154) expression is manifested on KCs and macrophages. The present novel data show another important cellular source of CD40L expression and suggest a potential role of KCs/macrophages and CD40/CD40L costimulatory interactions in the pathogenesis of chronic rejection ductopenic liver allograft.

Analysis of Intragraft Gene and Protein Expression of the Costimulatory Molecules, CD80, CD86 and CD154, in Orthotopic Liver Transplant Recipients

“…A number of investigators have previously shown increased expression of the costimulatory markers at the time of ACR (5,(8)(9)(10)(11)(15)(16)(17). In cardiac allografts, CD154 expression tended to be focal and predominately expressed on recipient graft infiltrating lymphocytes, but also to a less extent on donor endothelial cells (8).…”

“…In renal allografts the expression of CD80, CD86 and CD154 appear to follow a pathologically linked pattern (15). In liver allografts, CD154 expression has been shown to be increased on endothelial cells and mononuclear cells during acute and chronic rejection (9)(10)(11)18). In C, CD154 is predominately expressed on CD68-positive Kupffer cells and sinusoidal macrophages in a centrilobular distribution (9,11).…”

“…In liver allografts, CD154 expression has been shown to be increased on endothelial cells and mononuclear cells during acute and chronic rejection (9)(10)(11)18). In C, CD154 is predominately expressed on CD68-positive Kupffer cells and sinusoidal macrophages in a centrilobular distribution (9,11). This contrasted to the absence of CD154 expression in stable liver allografts and normal liver tissue (11).…”

Costimulatory blockade prevents early rejection, promotes lymphocyte apoptosis, and inhibits the upregulation of intragraft interleukin-6 in an orthotopic liver transplant model in the rat

“…[45][46][47][48][49][50][51] We previously showed that peripheral-blood mononuclear cells isolated from human liver transplant recipients administered calcineurin inhibitors had impaired CD154 expression after in vitro stimulation. 52 One possible explanation for this finding is that CD154 expression is at least partially dependant on the dephosphorylation of nuclear factor of activated T-cells (NF-AT), the target for calcineurin antagonists.…”

Immunology of Liver Transplantation

“…In DCs, CD40 upregulates interleukin12 (IL-12) production, and in macrophages it results in the production of various proinflammatory cytokines. CD154 was also detected on Kupffer cells and on sinusoidal macrophages in livers during chronic rejection, but not in stable liver allografts or normal liver (Gaweco A S et al, 1999).…”