Etanercept blocks inflammatory responses orchestrated by TNF-α to promote transplanted cell engraftment and proliferation in rat liver

Abstract

Engraftment of transplanted cells is critical for liver-directed cell therapy but most transplanted cells are rapidly cleared from liver sinusoids by proinflammatory cytokines/chemokines/receptors after activation of neutrophils or Kupffer cells. To define whether TNF-α served roles in cell-transplantation-induced hepatic inflammation, we used TNF-α antagonist, etanercept, for studies in syngeneic rat hepatocyte transplantation systems. After cell transplantation, multiple cytokines/chemokines/receptors were overexpressed, whereas etanercept prior to cell transplantation essentially normalized these responses. Moreover, ETN downregulated cell transplantation-induced intrahepatic release of secretory cytokines, such as high mobility group box 1. These effects of etanercept decreased cell transplantation-induced activation of neutrophils but not of Kupffer cells. Transplanted cell engraftment improved by several-fold in etanercept-treated animals. These gains in cell engraftment were repeatedly realized after pretreatment of animals with etanercept before multiple cell transplantation sessions. Transplanted cell numbers did not change over time indicating absence of cell proliferation after etanercept alone. By contrast, in animals preconditioned with retrorsine and partial hepatectomy, cell transplantation after etanercept pretreatment significantly accelerated liver repopulation compared with control rats. We concluded that TNF-α played a major role in orchestrating cell transplantation-induced inflammation through regulation of multiple cytokines/chemokines/receptor expression. As TNF-α antagonism by etanercept decreased transplanted cell clearance, improved cell engraftment and accelerated liver repopulation, this pharmacological approach to control hepatic inflammation will help optimize clinical strategies for liver cell therapy.

A genetic screen reveals Foxa3 and TNFR1 as key regulators of liver repopulation

“…The disparate findings with TNF signaling in promotion of regeneration after partial hepatectomy as opposed to inhibition of repopulation in the Fah −/− model may be due to a sensitivity to level of activation of TNF signaling, the duration of injury, or the inflammatory context in toxic liver injury. Interestingly, a recent study demonstrated that blockade of TNF signaling with etanercept promoted engraftment of transplanted hepatocytes in a rat model (Viswanathan et al 2014). Taken together, these data suggest that inhibition of TNFR1 expression or activity in hepatocytes may represent a novel strategy to promote healthy repopulation in the context of toxic liver injury.…”

Infliximab and Dexamethasone Attenuate the Ductular Reaction in Mice

“…Another aspect we did not consider in this study, is the use of other TNF-α-blocking agents such as adalimumab, golimumab17 or etanercept29 to determine whether one of these clinically approved monoclonal antibodies has a better efficiency and efficacy to abolish the DR and fibrosis. All these TNF-α blockers contain the IgG1 Fc portion, which on one hand improves the in vivo half-life, but on the other hand leads to unwanted effector-mediated cytotoxic effects.…”

Thalidomide promotes transplanted cell engraftment in the rat liver by modulating inflammation and endothelial integrity

“…For instance, early clearance of transplanted cells (80–90%) from the liver is a major problem for cell engraftment. Recently, ischemia-related events involving vasoconstrictors, such as endothelin (ET)-1 (2,3), and numerous inflammatory chemokines/cytokines/receptors controlled by cell transplantation-induced expression of TNF-α were determined to play significant roles in clearance of transplanted cells (4). On the other hand, to integrate in the liver parenchyma, transplanted cells must enter the space of Disse by disruption of liver sinusoidal endothelial cells (LSEC), which requires additional interventions and further contributes in clearance of transplanted cells (5).…”

“…If such cell transplantation-related deleterious events could be controlled especially by drugs that should particularly benefit clinical applications. In preclinical animal models of cell engraftment or liver repopulation, the beneficial potential of multiple discrete drug targets was successfully demonstrated, e.g., vasodilatation of hepatic sinusoids by nitroglycerine, phentolamine, prostacyclin or ET-1 receptor blockers, bosentan (BOS) and darusentan (2,3,6), release of cytoprotective factors from hepatic stellate cells (HSC) by the cyclooxygenase inhibitors, naproxen or celecoxib (7), neutralization of TNF-α expressed by neutrophils (PMN) or Kupffer cells (KC) by etanercept (ETN) (4), and induction of injury to LSEC with cyclophosphamide or doxorubicin (8,9). Similarly, availability of safe and effective drugs with more than one desirable mechanism of action could advance cell therapy strategies.…”

“…After gaining notoriety because of its early teratogenic toxicity, Thal has seen a substantial resurgence, and now constitutes a unique class of its own with multiple analogs displaying additional activities, e.g., degradation of substrates by ubiquitination (10,11). It should be relevant that in regards to the role after cell transplantation of PMN or KC-related expression of cytokines/chemokines/receptors as inflammatory mediators (2–4,12,13), Thal inhibited recruitment of these cell types to sites of inflammation, e.g., skin or liver (14,15), and also downregulated cytokine expression in inflammatory cells, including of TNF-α and interleukins (Il) (10). Moreover, Thal protected hepatocytes from alcohol- or other toxins (15–17).…”