NITRIC-OXIDE FORMATION AS PREDICTIVE PARAMETER FOR ACUTE GRAFT-VERSUS-HOST DISEASE AFTER HUMAN ALLOGENEIC BONE-MARROW TRANSPLANTATION

Due to the accumulation of evidence concerning a putative role of nitr ic oxide (NO) in graft-versus-host disease (GVHD), we performed follow -up measurements of the stable end-products of NO, nitrite/nitrate (NO 2-/NO3-) in plasma of patients undergoing allogeneic (n=16) and autolo gous (n=6, as a control) bone marrow transplantation. NO2-/NO3- concen trations were set in relation to the clinical course and to serum leve ls of soluble tumor necrosis factor receptor 75 (sTNFrec 75) and neopt erin, both of which are known to be sensitive indicators of cellular i mmune activation phenomena involving macrophages in vivo, and endogeno us interleukin (IL)-10, a major T helper cell type 2 (TH-2)-derived cy tokine and potent inhibitor of macrophage activation and NO formation. A significant rise of NO2-/NO3- levels was observed in patients with GVHD and preceded the onset of clinical symptoms by up to 3 days. In c ontrast to indicators of macrophage activation, i.e., neopterin and sT NFrec75, NO2-/NO3- concentrations were not significantly altered from baseline levels during infectious complications, as NO2-/NO3- concentr ations did not fluctuate in patients after autologous engraftment. Dur ing episodes of acute GVHD, NO2-/NO3- concentrations showed a strong p ositive correlation with levels of plasma neopterin and sTNFrec 75, bu t were also significantly related to IL-10. In non-GVHD patients, a ne gative correlation between IL-10 and NO2-/NO3- concentrations was evid ent. Therefore, NO2-/NO3- determination may be a valuable early indica tor of the initiation of human GVHD. Our results provide some further insights concerning cytokine-related metabolic changes in the course o f human GVHD in vivo which may prove useful in the development of new therapeutic approaches for this disease.