INCREASED NITRIC-OXIDE (NO) PRODUCTION BY ANTIGEN-PRESENTING DENDRITIC CELLS IS RESPONSIBLE FOR LOW ALLOGENEIC MIXED LEUKOCYTE REACTION (MLR) IN PRIMARY BILIARY-CIRRHOSIS (PBC)

The levels of blastogenesis in allogeneic MLR containing T cells from one normal volunteer and irradiated dendritic cells from 29 patients w ith PBC, 17 patients with chronic hepatitis type C (CH-C) and 22 allog eneic normal controls were compared to see if there is any role of ant igen-presenting cells (APC) in the pathogenesis of PBC. The stimulator y capacity of dendritic cells from PBC was significantly lower compare d with that of dendritic cells from CH-C (P < 0.05) and normal control s (P < 0.05), which could not be attributable either to the levels of expression of surface molecules, such as HLA-DR and CD86 on dendritic cells, or to the levels of cytokines, such as IL-10 and IL-12. Signifi cantly higher levels of NO were seen in the allogeneic MLR supernatant s containing dendritic cells from PBC compared with the supernatants f rom cultures containing dendritic cells from CH-C (P < 0.001) or norma l controls (P < 0.001). Moreover, dendritic cells from PBC produced 10 times more NO compared with dendritic cells from CH-C and normal cont rols (21.9 +/- 2.8 mu M versus 1.6 +/- 0.3 mu M and 1.6 +/- 0.3 mu M, respectively; P < 0.001). The addition of N-G-monomethyl-L-arginine mo noacetate (LNMMA), a known inhibitor of NO in allogeneic MLR containin g dendritic cells from PBC, resulted in a significant decrease of NO a nd increase of blastogenesis. The selective impairment of dendritic ce ll function, increased production of NO by dendritic cells and restora tion of blastogenesis using NO inhibitor in PBC have suggested a role for NO and dysfunction of dendritic cells in the pathogenesis of PBC. This inspires optimism that modulating the function of dendritic cells and controlling NO production, an improved therapeutic approach, migh t be planned for PBC.