Defective interleukin-1 receptor antagonist production is associated with resistance of acute liver graft rejection to steroid therapy

Thirty percent of acute liver graft rejection episodes are resistant to ste roids. As interleukin-1 (IL-1) is an important target of steroid therapy, w e examined the possible Involvement of reduced sensitivity of IL-1 producti on to steroids or defective production of its antagonist, IL-1Ra, Patients were assessed during steroid-sensitive or -resistant rejection and 2 years later. In situ IL-1 beta and IL-1Ra expression was evaluated by immunohisto chemistry; their production was assayed by enzyme-linked immunosorbent assa y and the gene polymorphisms by reverse transcriptase-polymerase chain reac tion on blood cells. Hepatic IL-1 beta and IL-1Ra expression were enhanced during rejection. IL-1 production and its inhibition by steroids were simil ar in steroid-responsive and steroid-resistant rejection. However, IL-1Ra p roduction was lower in steroid-resistant than in steroid-responsive rejecti on, and this difference was still observed 2 years after rejection. IL-1 be ta and IL-1Ra gene polymorphisms did not differ between patients with and w ithout steroid resistance. Low IL-1Ra production is associated with steroid resistance of acute rejection and is due to a constitutional defect. The e arly identification of such patients might qualify them for stronger antire jection therapy, Including IL-1Ra.