Injured erythrocytes release adenosine deaminase into the circulation.

The purpose of this study was to test the hypothesis that circulating red blood cells (RBCs) release adenosine deaminase (ADA) when injured. This hypothesis was evaluated in rats using dimethyl sulfoxide (DMSO) to damage RBCs. Boluses and infusions of DMSO caused a reduction in urinary adenosine and a concomitant hemoglobinuria, and the ability of DMSO to reduce urinary adenosine was blocked by pretreatment with the ADA inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine. Infusions of DMSO also significantly enhanced ADA activity in urine and plasma. Dimethylsulfone, an analog of DMSO that does not affect RBCs, did not cause hemoglobinuria and did not affect urinary adenosine. High concentrations of DMSO did not affect adenosine metabolism in rat kidneys perfused without RBCs, and DMSO did not decrease urinary adenosine in rats rendered severely anemic (hematocrit < 15%) by replacing whole blood with plasma. However, DMSO did decrease urinary adenosine in rats without a spleen, a major source of adenosine deaminase apart from circulating RBCs. DMSO reduced renal interstitial levels of adenosine and attenuated bradycardic responses to exogenous adenosine, and these effects were prevented by erythro-9-(2-hydroxy-3-nonyl)adenine. These results indicate that circulating damaged RBCs release significant amounts of ADA, a process that may predispose to vasoocclusive events.

FK506 (tacrolimus) in the treatment of steroid-resistant acute graft-versus-host disease in children undergoing bone marrow transplantation.

Steroid-resistant graft-versus-host disease (GVHD) is an often lethal complication of bone marrow transplantation (BMT). FK506 (tacrolimus) is a new potent immunosuppressant which has been shown to be superior to conventional immunosuppression in the prevention and treatment of graft rejection in recipients of solid organ transplants. To determine whether FK506 is effective in the treatment of steroid-resistant acute GVHD, 6 children with biopsy-proven severe GVHD were studied. FK506 was administered as intravenous or oral therapy and the dose was adjusted to achieve serum levels between 0.5 and 1.0 microgram/ml by ELISA. Steroid doses were tapered based on clinical grading in each organ. Within 1-2 days, improvement occurred in skin and gut in all patients, and in liver in 3 patients. Toxicity attributable to FK506 was similar to that described in solid organ transplant patients and included neurotoxicity, nephrotoxicity and gastrointestinal effects. While FK506 is effective in the treatment of steroid-resistant acute GVHD, toxicity may limit its use. Further studies evaluating FK506 as GVHD prophylaxis and treatment of less advanced GVHD are needed.