Significance of Post-Liver Transplantation Induced Anti-Histone H1 Antibody for Prevention of Chronic Rejection and Liver Fibrosis.

Objectives: Post-transplant chronic rejection and fibrosis is still the major two obstacles to obtain long-term survival in orthotopic liver transplantation (OLT). In order to prevent these complications, in clinical settings, administration of low-dose immunosuppressive drugs for long-term surviving OLT patients is preferred rather than complete withdrawal of immunosuppressant (drug-free). We have clinically and experimentally demonstrated that immunosuppressive anti-nuclear histone H1antibody(Ab) can be observed not only in a drug-free OLT patient but also in patients treated with a low-dose immunosuppressant.Our previous study has also demonstrated that anti-hitone H1 Ab lead to immature dendritic cells and to subsequently induce regulatory T cells. Methods: In the present study, we explored the role of histone H1 during hepatic fibrogenesis and investigated the functional effects of histone H1 gene silencing inhepatic stellate cells (HpSCs) activation. Results: We found that histone H1 was upregulated during liver fibrosis and that its expression was closely correlated with the deposition of collagen fibers. Inhibition of histone H1 by small interfering RNA (siRNA) in HpSCs suppressed synthesis of α-smooth muscle action (SMA) and collagen type I. Conclusions: These results suggest that histone H1 may implicate in the development of liver fibrosis and it may be novel therapeutic target for repressing liver fibrosis. Additionally, post-transplant elevation of immunosuppressiveanti-histone H1 Ab in OLT patients treated with low-dose immunosuppressant may contribute to not only inhibit chronic rejection but alsorepress liver fibrosis.