In vivo blockade of tumor necrosis factor-alpha in cholesterol-fed rabbits after cardiac transplant inhibits acute coronary artery neointimal formation.

Abstract

BACKGROUND We previously identified in piglet cardiac allografts an immunoinflammatory response in coronary arteries in which increased fibronectin regulated by interleukin-1 beta was associated with early evidence of intimal thickening. In the present study, we used rabbits to assess whether acute neointimal formation after cardiac transplantation was reduced by blockade of tumor necrosis factor (TNF)-alpha, which modulates interleukin-1 beta, or by cyclosporine A. METHODS AND RESULTS Sixteen rabbits underwent heterotopic cardiac transplantation and were given saline, TNF-soluble receptor (sr), or cyclosporine A. In host hearts from saline- or TNFsr-treated groups, few coronary arteries (approximately 13% to 16%) had intimal thickening, whereas values were higher in the cyclosporine A-treated group (approximately 30%). In donor hearts from the saline-treated group, however, approximately 68% of vessels had intimal thickening versus approximately 32% in TNFsr- and approximately 30% in cyclosporine A-treated groups (P < .01 for both). Severity of intimal thickening assessed quantitatively as percent vessel area was approximately 38% in the saline-treated group but reduced in TNFsr- and cyclosporine A-treated groups to approximately 22% and 18%, respectively (P < .01 for each). Immunohistochemistry revealed increased staining for major histocompatibility complex II, T cells, interleukin-1 beta, TNF-alpha, and fibronectin in donor coronary arteries from saline-treated animals when compared with TNFsr- and cyclosporine A-treated animals. Grade 3 myocardial rejection was observed in both saline- and TNFsr-treated groups, but only grade 1 was apparent in the cyclosporine A-treated group. CONCLUSIONS In vivo blockade of TNF-alpha suppresses the acute development of neointimal formation by selectively reducing the vascular immunoinflammatory reaction and accumulation of fibronectin, whereas cyclosporine A suppresses both the myocardial and the vascular immune reaction.

Restoration of E2F Expression Rescues Vascular Endothelial Cells From Tumor Necrosis Factor-α–Induced Apoptosis

“…20,21 Blockade of TNF-␣ resulted in significantly accelerated reendothelialization of the injured carotid artery segments compared with control (IgG-treated) arteries ( Figure 1A and 1B). These results provide support in vivo for a significant negative effect of TNF-␣ on proliferating endothelial cells at sites of arterial injury.…”

“…This soluble receptor molecule previously has been shown to neutralize human, rodent, and rabbit TNF-␣ in vitro and in vivo. 20,21 The dosage used (2.5 mg/kg IP every 3 days) was chosen on the basis of previously published studies and a pilot series performed in our laboratory.…”

Modulation of Autoimmunity and Atherosclerosis – Common Targets and Promising Translational Approaches Against Disease –

“…36 Notably, anti-TNF therapy is associated with lower CVD risk in RA 37,38 and psoriatic patients. 39 Experimentally, TNF blockade in vivo suppresses neointimal formation in the coronary arteries of transplanted hearts, 40 but not following balloon angioplasty in rabbits. 41 In atherosclerosis-prone hypercholesterolemic Apoe -/-mice, TNF deficiency or blockade mitigates atherosclerosis, 42 suggesting that this therapy could potentially have beneficial effects on CVD in the general population.…”

In Vivo Blockade of Tumor Necrosis Factor-α Accelerates Functional Endothelial Recovery After Balloon Angioplasty

“…This soluble receptor molecule has previously been shown to neutralize human, rodent, and rabbit TNF in vitro and in vivo. 9 The dosage used (2.5 mg/kg IP every 3 days) was chosen on the basis of previously published studies and a pilot series performed in our laboratory.…”