Immunological Changes Of Primary Biliary Cirrhosis After Drug Therapy

Objective To prospectively study the therapeutic effects of ursodeoxycholic acid(UDCA) and UDCA combined with prednisolone in patients with primary biliary cirrhosis(PBC),and analyze the expression characteristic of biochemical determinations, serum immunoglobulins,peripheral blood lymphocyte subsets,cytokines,and autoantibodies (anti-mitochondrial antibody,M2 anti-mitochondrial antibody,anti-GP210 antibodies and anti-SP100 antibodies) after treatment.Methods 30 patients(1 man and 29 women,aged from 30 to 72,average aged at 52.33±8.77) were included according to the guideline for management of PBC presented by AASLD in 2000,who all signed informed consent before treatment.All patients had been treated with UDCA(Group U,20 patients) or UDCA combined with prednisolone(Group UP,10 patients) for at least 2 years.The drug dosage of UDCA was 13-15mg/kg/d,and that ofprednisolone was 0.5mg/kg/d in the beginning,then gradually decreased to7.5mg/d since the 4^th week.Clinical and laboratory data of these patients were collected before the treatment,3 months,6 months and over 24 months after treatment,including liver biochemical function(including ALT,AST,GGT,ALP,TBIL,DBIL,TBA,ALB),white blood cells,immunoglobulins(including IgG,IgA,IgM), lymphocytic subsets(including B cells,NK cells,T cells,CD3+CD4+T cells,CD3+CD8+ T cells,CD4+CD28+T cells,CD4+CD28-T cells,CD8+CD28+T cells,CD8+CD28 -T cells,CD4+CD25+T cells),cytokines(including TNF-α,IL-1β,IL-2,IL-4,IL-6, IL-10) and autoantibodies(AMA,AMA-M2,anti-GP210 antibody,anti-SP 100 antibody). Results The levels ofALT(P=0.001 in group U;P=0.016 in group UP),AST(P=0.009 in group U),ALP(P=0.018 in group UP) and GGT(P=0.027 in group UP) decreased in both group U and group UP after treatment.The levels of ALT and ALP in group U decreased rapidly and were obviously lower than that in group UP(P=0.016 and P=0.039 respectively) after three-month treatment.The above difference disappeared as the treatment went on. There was no significant change in the levels of IgG,IgA,IgM,WBC and lymphocytic subsets in either group U or group UP after treatment(P＞0.05).The levels of IL-2,IL-4, IL-6,IL-10,TNF-αand IL-1βin the peripheral blood of patients with PBC decreased in both group U and group UP as time went by(P＜0.05),which was especially significant when the time of therapy was over 24 months.Among the 30 patients,90%of the patients were detected with positive AMA and 73.33%with AMA-M2.There was no significant change in the titer of AMA or the level of AMA-M2 in either group after treatment(P＞0.05).33.3% and 16.67%of patients had positive anti-GP210 antibody and anti-SP100 antibody, respectively.The levels of ALT,AST,ALP and IgM among patients with negative anti-GP210 antibody gradually decreased after treatment(P=0.000,P=0.000,P=0.014 and P=0.039,respectively) as time went by.The levels of ALT,AST,ALP and GGT among patients with negative anti-SP100 antibody decreased significantly after treatment(P=0.007, P=0.015,P=0.005 and P=0.048,respectively) as time went by.Correlation test showed that levels of ALT,AST,ALP and GGT were correlated positively with different cytokines on certain level(P＜0.05).The levels of IL-1βand IL-10 were correlated positively with the percentages of lymphocytes and CD8+CD28+T cells while negatively with the percentage of CD8+CD28-T cells(P＜0.05).There was a positive correlation between anti-GP210 antibody and the levels of AST,DB,TBA,IgA and IgM(P＜0.05),while a negative correlation appeared between anti-SP 100 antibody and the level of IgG(P＜0.05). Conclusions 1.Both UDCA monotherapy and UDCA combined with prednisolone could improve part of the liver function of the patients with PBC.Considering the side effects, UDCA monotherapy is still the first-choice treatment.2.There is no regulative effect of the two therapies on expressions of immunoglobulins,Th1 and Th2 lymphocytes,CD8+CD28 -regulatory T cells,CD4+CD25+ regulatory T cells,NK cells and B cells in patients with PBC.3.Both of the two therapies could slowly inhibit the levels of Th1 cytokine-IL-2, and low-level IL-2 could inhibit the activation of T lymphocytes.4.Both of the two therapies could slowly inhibit the levels of Th2 cytokines-IL-4,IL-6,IL-10,and their decrease could inhibit the activation of B cells and the lesions due to higher immune reactions to autoantigens.5.Both of the two therapies could slowly inhibit the levels of TNF-αand IL-1β,and the reduction of TNF-αand IL-1βmight relieve the inflammatory injury of the liver,suppress the inflammatory reaction and delay the pathological lesions of the liver.6.AMA,AMA-M2 is the biomarker of PBC,but there is no relationship between them and the states of the illness.There is a relationship between anti-GP210 antibodies and the state of PBC,and the level of anti-GP210 antibodies could be used to assess the severity of PBC.Patients with positive anti-GP210 antibody and anti-SP100 antibody have bad reaction towards drug therapy,thus they could be used for prediction of the therapeutic effects.