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 steroids. As interleukin-1 (IL-1) is an important target of steroid therapy, we examined the possible involvement of reduced sensitivity of IL-1 production 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-1beta and IL-1Ra expression was evaluated by immunohistochemistry; their production was assayed by enzyme-linked immunosorbent assay and the gene polymorphisms by reverse transcriptase-polymerase chain reaction on blood cells. Hepatic IL-1beta and IL-1Ra expression were enhanced during rejection. IL-1 production and its inhibition by steroids were similar in steroid-responsive and steroid-resistant rejection. However, IL-1Ra production was lower in steroid-resistant than in steroid-responsive rejection, and this difference was still observed 2 years after rejection. IL-1beta and IL-1Ra gene polymorphisms did not differ between patients with and without steroid resistance. Low IL-1Ra production is associated with steroid resistance of acute rejection and is due to a constitutional defect. The early identification of such patients might qualify them for stronger anti-rejection therapy, including IL-1Ra.
Conti
F
F
Laboratoire de Biologie Cellulaire, Faculté de Médecine Cochin-Port-Royal, Université Paris, Paris, France.
Breton
S
S
Batteux
F
F
Furlan
V
V
Houssin
D
D
Weill
B
B
Calmus
Y
Y
D000208:Acute Disease; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D004351:Drug Resistance; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012016:Reference Values; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics; D013997:Time Factors
D000305:Adrenal Cortex Hormones; C507763:IL1RN protein, human; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D016572:Cyclosporine; D001379:Azathioprine