Chronic allograft vasculopathy: new strategies for drug development

Chronic rejection reflects cumulative trauma to the allograft regardless of its origin. The main histologic feature in chronic rejection in all allografts is proliferative allograft vasculopathy. According to the current paradigm, chronic rejection can be prevented by more intensive and selective immunosuppression. Experimental retransplantation to donor strain suggests that elimination of histoincompatibility does not prevent progression of the disorder after the initial stimulus has been sufficiently strong or long-lasting. In order to design additional sites for intervention after this point of no return, attention has focused on the regulation of the synthesis and/or action of smooth muscle cell growth factors. In several preclinical models, the blocking of growth factor synthesis, blocking of the binding of the growth factors to their receptors, and/or growth factor signaling downstream of the receptor, have successfully been used in the inhibition of the intimal response and allograft vasculopathy. Inhibition of proteolytic enzymes, necessary for smooth muscle cell locomotion, may provide additional sites of intervention. However, on most occasions, the inhibitory effect is incomplete only 30% to 50% of maximal. The future will demonstrate whether several approaches must be applied concomitantly, or whether genes regulating several of these ligands and their receptors simultaneously can be identified and exploited.