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. (Circulation. 1994;89:2768-2779.)