calcimycin and Liver-Diseases--Alcoholic

Immune system derangement is characteristic of alcoholic liver cirrhosis. However, in vitro studies have never clarified the alcohol-induced T-lymphocyte dysfunction. The aim of this study was to examine any discrete phenotypical and functional abnormalities and possible impairment in transmembrane signal-transduction pathways that, if present on lymphocytes of patients with alcoholic cirrhosis, would also be reproducible after in vitro ethanol exposure of normal T cells.. Lymphocytes from 25 patients were analyzed for their in vitro proliferative functions, intracellular Ca2+ fluxes, and inositol 1,4,5-triphosphate (IP3) generation. The same procedures were applied to normal T cells exposed in vitro to ethanol.. Lymphocytes failed to respond to anti-CD3 and anti-CD2 after in vitro stimulation, with decreased intracellular Ca2+ mobilization and IP3 generation but showed normal proliferative response to phytohemagglutinin. In vitro ethanol incubation of normal T lymphocytes resulted in rearrangement of the membrane CD45 antigen, favoring the expression of high-molecular-weight isoforms, and showed a poor blastogenic response to anti-CD3 and anti-CD2 with a decrease in intracellular Ca2+ mobilization and IP3 production. After a 6-month period of ethanol withdrawal, some patients had normalization of phenotypic and functional alterations.. The T-lymphocyte response to specific polyclonal activators may be severely impaired in alcohol abusers. However, it seems reversible after a period of controlled ethanol withdrawal.

Topics: Adult; Antigen-Presenting Cells; Antigens, CD; Calcimycin; Calcium; Cells, Cultured; Ethanol; Female; Humans; Inositol 1,4,5-Trisphosphate; Interleukin-1; Interleukin-2; Liver Diseases, Alcoholic; Lymphocyte Activation; Male; Middle Aged; Signal Transduction; T-Lymphocytes; Tetradecanoylphorbol Acetate

Immune system derangement in cirrhotic patients with evidence of malnutrition is a well-recognized characteristic of chronic alcohol abuse. However, in vitro studies on cellular immune function performed with lectin mitogens have produced conflicting results. The recent development of more accurate immunological techniques for studying lymphocyte transformation, that use monoclonal antibodies directed against surface structures (CD3 and CD2) involved in antigen recognition, as well in adhesion functions, prompted us to study discrete in vitro T-cell hypo-responsiveness in a series of alcoholic liver disease (ALD) patients with no evidence of malnutrition or hepatic cirrhosis. The results indicated that the CD2 pathway is markedly defective in ALD T lymphocytes, accompanied by reduced interleukin-2 (IL-2) receptor expression upon in vitro activation. This defect cannot be reversed by the addition of recombinant IL-2 (rIL-2) or rIL-1. Faulty intracellular signal transduction by protein kinase C (PKC) and defective intracellular Ca2+ mobilization may be responsible for the CD2 pathway impairment. The addition of small amounts of phorbol 12-myristate, 13-acetate, but not Ca2+ ionophore A23187, is able to overcome the defect, thereby suggesting a direct PKC involvement. The hypothesis of a direct ethanol effect on transmembrane signal transduction systems is suggested by the demonstration of an expansion of circulating virgin (naive) T cells (CD3+/UCHL1-low) that binds tyrosine phosphatase (CD45RA antigen) on their surface.

Topics: Adult; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Antigens, Surface; Calcimycin; CD2 Antigens; CD3 Complex; Cell Division; Female; Humans; Interleukins; Liver Diseases, Alcoholic; Lymphocyte Activation; Male; Middle Aged; Phytohemagglutinins; Receptors, Antigen, T-Cell; Receptors, Immunologic; T-Lymphocytes; Tetradecanoylphorbol Acetate