Decreased infiltration of CD4+ Th1 cells indicates a good response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis

Abstract

Background: Primary biliary cholangitis (PBC) is characterized by nonsuppurative destructive cholangitis and is thought to be an autoimmune disorder. Currently, ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to nearly one-third of patients do not achieve a complete response to this treatment. Adaptive immune cells, including T cells and B cells, have been found in the portal tracts and the bile duct epithelium and play a role in the pathogenesis of PBC, but the importance of these cells for evaluating the therapeutic response to UDCA in PBC has not yet been studied.

Methods: In this study, we collected liver puncture biopsy specimens from 34 matched patients with PBC before and after UDCA treatment and investigated the relationship between the infiltration of adaptive immune cells and the treatment response to UDCA. The extent of immune cell infiltration was determined by immunohistochemical analysis. Responses were defined based on Paris-I criteria.

Results: After 1 year of treatment, 25/34 patients responded to UDCA treatment according to Paris-I criteria (responders), and 9/34 patients were nonresponders. Immunohistochemical analysis showed that UDCA responders exhibited significantly less CD4⁺ T cell infiltration after UDCA treatment than before (50.4 ± 7.5/HPF vs 30.0 ± 7.9/HPF, P = 0.002). In contrast, UDCA nonresponders exhibited significantly more CD4⁺ T cell infiltration after UDCA treatment than before (32.2 ± 8.0/HPF vs 75.0 ± 13.9/HPF, P = 0.045). Moreover, patients who exhibited a reduction in CD4⁺ T cell infiltration after UDCA treatment had a higher response rate than those that exhibited an increase in CD4⁺ T cell infiltration (85.7 % vs 53.8 %, P = 0.041). However, CD3⁺ T cell, CD8⁺ T cell, and CD20⁺ B cell infiltration was not significantly different before and after treatment in either UDCA responders or nonresponders. Furthermore, we found that the number of infiltrating T-bet⁺ Th1 cells was much lower after UDCA treatment than before in responders (10.5 ± 5.7/HPF vs. 5.16 ± 4.0/HPF, P = 0.0214) but much higher in nonresponders after treatment than before (1.89±1.2/HPF vs. 12.3±5.4/HPF, P = 0.043). However, there was no difference in the extent of GATA3⁺ Th2 or FOXP3⁺ Treg infiltration before and after treatment in either UDCA responders or nonresponders.

Conclusion: Collectively, our results suggest that a decrease in the number of liver-infiltrating CD4⁺ Th1 cells is associated with a good response of PBC patients to UDCA treatment. Immunohistochemical analysis of CD4 and T-bet in PBC liver specimens may be a potential approach for evaluating the therapeutic response to UDCA.

Keywords: Liver-infiltrating immune cells; Primary biliary cholangitis (PBC); Therapeutic response; Ursodeoxycholic acid (UDCA).