Utsumi Masashi, Takaki Akinobu, Umeda Yuzo, Koike Kazuko, Napier Stephanie C, Watanabe Nobukazu, Sadamori Hiroshi, Shinoura Susumu, Yoshida Ryuichi, Nobuoka Daisuke, Yasunaka Tetsuya, Nakayama Eiichi, Yamamoto Kazuhide, Fujiwara Toshiyoshi, Yagi Takahito
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
Transpl Immunol. 2014 Jun;31(1):33-41. doi: 10.1016/j.trim.2014.05.006. Epub 2014 Jun 5.
Regulatory T (Treg) and type 1 regulatory T (Tr1) cells facilitate hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT). However, their frequencies and effects on HCV-specific immune responses have not been well investigated.
We determined Treg and Tr1 frequencies in OLT patients with hepatitis C and assessed their associations with HCV-specific T cell responses. These patients comprised the following groups: an early post-transplantation group (n=14); an OLT-chronic active hepatitis C group (n=14) with active hepatitis C (alanine aminotransferase of>upper limit of normal/positive for HCV-RNA); an OLT-persistently normal alanine aminotransferase group (n=12) without active hepatitis C (not interferon/positive for HCV-RNA); and an OLT-sustained viral response group (n=6) with sustained viral responses using interferon treatment (negative for HCV-RNA). The frequencies of HCV-specific CD4+ T cells that secreted interferon-γ were determined by enzyme-linked immunosorbent spot assay (except for the OLT early group).
Treg and Tr1 frequencies were low during the early post-transplantation period. OLT patients with sustained viral responses had lower Treg frequencies than those with chronic hepatitis C, whereas Tr1 frequencies were significantly reduced in OLT patients with persistently normal alanine aminotransferase levels compared to those with chronic hepatitis C (p<0.05). Treg frequencies positively correlated with HCV NS3 antigen-specific interferon-γ responses, which corresponded to HCV clearance.
Increased Treg frequencies and reduced HCV-NS3 antigen-specific responses recovered after viral eradication in post-OLT chronic hepatitis C patients. Reduced Tr1 frequencies were associated with hepatitis activity control, which may facilitate controlling chronic hepatitis C in patients after OLT.
调节性T（Treg）细胞和1型调节性T（Tr1）细胞促进原位肝移植（OLT）后丙型肝炎病毒（HCV）复发。然而，它们的频率及其对HCV特异性免疫反应的影响尚未得到充分研究。
我们测定了丙型肝炎OLT患者的Treg和Tr1频率，并评估了它们与HCV特异性T细胞反应的相关性。这些患者包括以下几组：移植后早期组（n = 14）；OLT-慢性活动性丙型肝炎组（n = 14），患有活动性丙型肝炎（丙氨酸氨基转移酶>正常上限/HCV-RNA阳性）；OLT-丙氨酸氨基转移酶持续正常组（n = 12），无活动性丙型肝炎（非干扰素/HCV-RNA阳性）；以及OLT-持续病毒应答组（n = 6），使用干扰素治疗后有持续病毒应答（HCV-RNA阴性）。通过酶联免疫吸附斑点试验测定分泌干扰素-γ的HCV特异性CD4 + T细胞的频率（OLT早期组除外）。
移植后早期Treg和Tr1频率较低。持续病毒应答的OLT患者的Treg频率低于慢性丙型肝炎患者，而与慢性丙型肝炎患者相比，丙氨酸氨基转移酶水平持续正常的OLT患者的Tr1频率显著降低（p<0.05）。Treg频率与HCV NS3抗原特异性干扰素-γ反应呈正相关，这与HCV清除相对应。
OLT后慢性丙型肝炎患者病毒根除后，Treg频率增加，HCV-NS3抗原特异性反应恢复。Tr1频率降低与肝炎活动控制相关，这可能有助于控制OLT后患者的慢性丙型肝炎。
