Tumour necrosis factor alpha impairs function of liver derived T lymphocytes and natural killer cells in patients with primary sclerosing cholangitis

Background-Primary sclerosing cholangitis (PSC) is considered to be a chron ic autoimmune disease where infiltrating T lymphocytes have been implicated in the destruction of bile ducts. Altered function of these T cells may re flect abnormalities in the immune response leading to tissue damage. Aim-We investigated the proliferative and functional capacity of freshly is olated liver derived T lymphocytes (LDLs) and natural killer (NK) cells fro m PSC patients. Methods-The proliferative responses to common mitogens such as phytohaemagg lutinin (PHA), concanavalin A (Con A), and lipopolysaccharide (LPS) were st udied, and the cytotoxic function of T lymphocytes was measured using allog eneic target cells. NK (CD56(+)/16(+)) cytotoxic function was measured usin g the two cell lines K562 (NK sensitive) and Raji lymphoma cells (NK resist ant). Results-Compared with patients with primary biliary cirrhosis (PBC), autoim mune hepatitis (AIH), and normal controls (without Liver disease), in PSC: (1) LDLs contained a low percentage of T cells; (2) there was significantly decreased expression of interleukin (IL)-2 receptor (p<0.001) on activated T cells (HLA-DR+); (3) LDLs but not peripheral blood lymphocytes had signi ficantly impaired proliferative responses to mitogens such as PHA, Con A, a nd LPS (p<0.001); (4) no cytotoxic activity of PSC Liver T and NK cells was recorded; (5) significantly higher levels of tumour necrosis factor a alph a (TNF-alpha) and IL-1 beta but lower levels of IL-2, IL-10, and interferon gamma were found in the supernatants of mitogen stimulated LDL cultures (p <0.001); (6) higher percentages of freshly isolated PSC LDLs contained intr acytoplasmic TNF-<alpha> and IL-1 beta; and (7) pretreatment of PSC LDLs in vitro with neutralising TNF antibodies significantly enhanced proliferativ e responses and allowed IL-2 receptor expression following stimulation. In addition, the impaired cytolytic activity of both NK and T cells was partia lly restored. Impaired proliferative or functional capacity of liver derive d T cells was not observed in either PBC or AIH patients. Conclusions-We suggest that reduced T cell reactivity in liver infiltrating cells obtained from patients with PSC is due to high local production of T NF-alpha. Our findings indicate that the use of anti-TNF antibodies as an a lternative treatment for PSC patients should be evaluated.