Increased nitric oxide (NO) production by antigen-presenting dendritic cells is responsible for low allogeneic mixed leucocyte reaction (MLR) in primary biliary cirrhosis (PBC)

Abstract

The levels of blastogenesis in allogeneic MLR containing T cells from one normal volunteer and irradiated dendritic cells from 29 patients with PBC, 17 patients with chronic hepatitis type C (CH-C) and 22 allogeneic normal controls were compared to see if there is any role of antigen-presenting cells (APC) in the pathogenesis of PBC. The stimulatory capacity of dendritic cells from PBC was significantly lower compared with that of dendritic cells from CH-C (P < 0.05) and normal controls (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. Significantly higher levels of NO were seen in the allogeneic MLR supernatants containing dendritic cells from PBC compared with the supernatants from cultures containing dendritic cells from CH-C (P < 0.001) or normal controls (P < 0.001). Moreover, dendritic cells from PBC produced 10 times more NO compared with dendritic cells from CH-C and normal controls (21.9 +/- 2.8 microM versus 1.6 +/- 0.3 microM and 1.6 +/- 0.3 microM, respectively; P < 0.001). The addition of N(G)-monomethyl-L-arginine monoacetate (L-NMMA), a known inhibitor of NO in allogeneic MLR containing dendritic cells from PBC, resulted in a significant decrease of NO and increase of blastogenesis. The selective impairment of dendritic cell function, increased production of NO by dendritic cells and restoration 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, might be planned for PBC.

Nitric Oxide Inhibits the Tumor Necrosis Factor α-regulated Endocytosis of Human Dendritic Cells in a Cyclic GMP-dependent Way

“…To our knowledge, iNOS expression and NO generation by these cells have not been reported, except in primary biliary cirrhosis and hepatocellular carcinoma (31,32). Consistently, we could detect neither expression of iNOS nor NO generation by human DC exposed to various combinations of cytokines and LPS.…”

“…After egress from the inflammation site, DC would no longer be exposed to NO and could therefore down-regulate their endocytic ability to prevent any interference by irrelevant selfantigens captured during migration to lymphoid organs (1). In conclusion, NO, acting on human DC in a paracrine fashion, may contribute to enhance immune responses, whereas disregulation of its homeostasis, with its generation under severe pathological conditions in DC (31,32), might instead impair the immunological function of these cells.…”

Effect of a cancer vaccine prepared by fusions of hepatocarcinoma cells with dendritic cells

“…Much data in recent years show that DC played a very important role in the tumor immune response [35][36][37][38][39] , especially with the develpment of gene therapy against tumor specific antigen. But at present, T cells epitopes of tumor specific antigens in most of the human cancers besides melanoma, breast cancer and ovarian cancer are not very clear [40] .…”

Prophylactic effect of <i>Withania somnifera</i> on inflammation in a non-autoimmune prone murine model of lupus

“…NO levels were assessed by measuring nitrite levels in the ascitic fluid and serum using Griess reagent (0.1% naphthylenediamineHCl/1% sulfanilamide in 5% phosphoric acid; 1:1, v/v) (18). The pink color produced by nitrite (the stable end product of NO metabolism) with Griess reagent was read at 540 nm.…”