Anti-CD20 Therapy Alters the Protein Signature in Experimental Murine AIH, but Not Exclusively towards Regeneration

Abstract

Background: Autoimmune hepatitis (AIH) is a chronic autoimmune inflammatory disease that usually requires lifelong immunosuppression. Frequent recurrences after the discontinuation of therapy indicate that intrahepatic immune regulation is not restored by current treatments. Studies of other autoimmune diseases suggest that temporary depletion of B cells can improve disease progression in the long term. Methods: We tested a single administration of anti-CD20 antibodies to reduce B cells and the amount of IgG to induce intrahepatic immune tolerance. We used our experimental murine AIH (emAIH) model and treated the mice with anti-CD20 during the late stage of the disease. Results: After treatment, the mice showed the expected reductions in B cells and serum IgGs, but no improvements in pathology. However, all treated animals showed a highly altered serum protein expression pattern, which was a balance between inflammation and regeneration. Conclusions: In conclusion, anti-CD20 therapy did not produce clinically measurable results because it triggered inflammation, as well as regeneration, at the proteomic level. This finding suggests that anti-CD20 is ineffective as a sole treatment for AIH or emAIH.

Splenectomy induces biochemical remission and regeneration in experimental murine autoimmune hepatitis

“…Similarly, others have demonstrated a mechanism by which cross-priming by LSECs results in tolerance in CD8 + T cells [ 34 ]. In contrast, the roles of the B-cell population and increased IgG and autoantibody levels are still not understood [ 16 , 35 – 37 ]. This is particularly noteworthy because the different autoantibody patterns have high diagnostic value and because depletion of B cells improves the course of disease in AIH models [ 10 , 11 , 16 , 37 ].…”

“…In contrast, the roles of the B-cell population and increased IgG and autoantibody levels are still not understood [ 16 , 35 – 37 ]. This is particularly noteworthy because the different autoantibody patterns have high diagnostic value and because depletion of B cells improves the course of disease in AIH models [ 10 , 11 , 16 , 37 ]. Unfortunately, the role of B cells could not be determined in this model of splenectomy in emAIH.…”

“…Subsequently, lymphocytes were stained with anti-CD3, anti-CD4, anti-CD8, anti-Ki-67, anti-B220, anti-Foxp3, and anti-CD62L antibodies. All image acquisitions were performed with an LSRII SORP interfaced with DIVA software (BD Biosciences) as described previously [ 16 , 19 ].…”

“…The alternatives studied in small local cohorts of patients include infliximab (anti-TNF-a), rituximab (anti-CD20) and low-dose IL-2 treatment. Recently, the latter therapies have shown good results in emAIH [ 15 , 16 ]. Additionally, in the 1960s, some patients with chronic hepatitis were treated by splenectomy with reasonable success rates [ 17 , 18 ].…”

Antidepressants cheer up hepatic B1 B cells: Hope for the treatment of autoimmune liver diseases?

“…Further studies support this view by showing that treatment of AIH patients with Rituximab or Belimumab (BAFF inhibitor) are effective in treating the condition ( 37 , 38 ). In contrast, recent evidence also shows that B cell depletion by Rituximab in experimental murine AIH reduces B cell numbers and IgG levels, but does not improve pathology indicating a discrepancy between human AIH and certain experimental mouse models ( 55 ). Furthermore, B cell depletion leads to a systemic immunosuppression which may abolish any protective effect of hepatic B1 B cells.…”