The Immune Modulatory Mechanisms Of Autoimmune Liver Disease And The Therapeutic Study Of The Inhibitor Of DNA Damage Repair Enzyme MTH1

PART 1 The role and mechanistic study of TH1579 in ameliorating immune-mediated liver injuryOBJECTIVE To explore the mechanism of MTH1 inhibitor TH1579 in treating AIH.METHODS To detect MTH1 in AIH patients through IHC,Laser confocal and Flow Cytometry,to explore the possible mechanism of MTH1 inhibitor TH1579 on adjusting the function of T cells.RESULTS The liver tissues of AIH patients showed massive expression of MTH1.T cells,which played important roles in the pathogenesis of AIH,expressed MTH1.In animal experiments,TH1579 inhibited the activation of T cells and altered the proportion of na(?)ve and memory T cells in splenocyte.In vitro experiments,TH1579 inhibited T cell proliferation by suppressing the expression of Cyclin E and CDK2,while enhancing the expression of P21 and P27.TH1579 may exert its function by inhibiting the activation of NF-κB.CONCLUSIONS The liver tissues of AIH patients expressed MTH1 abundantly.The liver inflammation could be ameliorated after inhibiting MTH1 by suppressing NF-κB and restraing the activation,proliferation and effector function of T cells,implying the critical role of MTH1 played in immune-mediated liver injury and were expected to be a new specific target for the treatment of immune-mediated liver injury in the future.PART 2 The immunobiology of MAIT cells in IgG4-SCObjective To explore the function and phenotype change of MAIT cells in IgG4-SC.Methods To detect the frequency,phenotype and function of MAIT cells in 18 healthy controls and 18 patients through flow cytometry.ResuLts Compared to healthy controls,the frequency of circulating MAIT cells is significantly lower in age and sex matched IgG4-SC patients(3.72±0.68% vs 1.03±0.17%,P<0.001).Besides,the cytokines produced by MAIT cells in IgG4-SC patients have been altered.In IgG4-SC patients,the frequency of Granzyme B,IFN-γ,TNF-αproducing MAIT cells has been sharply increased respectively(1.82± 0.66 % vs13.78±5.09%,P<0.05;11.72±1.93% vs 21.03±2.97%,P<0.05;4.98±1.20% vs 18.07±3.19%,P<0.001),while the level of IL-17 shows no difference between the two groups(1.10±0.38% vs 1.07±0.23%,P=0.9615).In addition,the homing ability of circulating MAIT cells to liver in IgG4-SC is enhanced.Circulating MAIT cells from IgG4-SC patients demonstrated a significant up-regulation of CXCR6 when compared to healthy controls(36.25 ±6.54 % vs 13.53±1.36%,P<0.001).Conclusion Circulating MAIT cells homed to and accumulated in inflamed liver to affect the progression of IgG4-SC.