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2)对慢性小三阳中二大类(肝功能正常和肝功能不正常)HBV感染者研究发现,肝功能正常病人(慢性肝炎静止期)有明显的HBV特异性免疫,肝内HBV特异性免疫的CD4+和CD8+T淋巴细胞多见,而肝功能不正常病人(慢性肝炎活动期)缺乏/没有HBV特异性免疫,肝内取而代之的是非特异性淋巴细胞和其他炎症细胞而致肝损伤。贺普丁治疗活动期慢乙肝发现使肝功能化同时,机体HBV特异性免疫功能恢复(原因是抗病毒复制后病毒抗原减少,而所受抑的免疫功能恢复)。此一研究再次表明,乙肝特异性免疫与肝损伤没有关系,HBV清除与肝损伤(非特异免疫反应所致)没有直接关系。
Maini MK, Boni C, Ogg GS, King AS, Reignat S, Lee CK, Larrubia JR, Webster GJ, McMichael AJ, Ferrari C, Williams R, Vergani D, Bertoletti A.
Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection.
Gastroenterology 1999 Dec;117(6):1386-96
BACKGROUND & AIMS: Cytotoxic T cells have been suggested to be responsible for lysis of hepatitis B virus (HBV)-infected hepatocytes and control of virus infection. The frequency, kinetics, phenotype, and capacity for clonal expansion of circulating HBV-specific CD8 cells were analyzed directly in patients with acute HBV infection to clarify their pathogenetic role.
METHODS: Three HLA-A2 peptide tetramers able to visualize HBV core, envelope, and polymerase epitope-specific cytotoxic T lymphocytes were synthesized and used for flow cytometric analysis of antigen-specific populations.
RESULTS: Tetramer-positive cells specific for the core 18-27 epitope were found at a higher frequency than those specific for polymerase 575-583 and envelope 335-343 epitopes in most patients with acute HBV. The number of HBV-specific CD8 cells was highest during the clinically acute stage of infection and decreased after recovery. These cells expressed an activated phenotype and had an impaired capacity to expand in vitro and to display cytolytic activity in response to peptide stimulation. Recovery of these functions was observed when the frequency of specific CD8 cells decreased, coincident with a progressive decrease in their expression of activation markers.
CONCLUSIONS: This study provides the first ex vivo evidence that the highest frequency of circulating HBV-specific CD8 cells coincides with the clinically acute phase of hepatitis B. These cells exhibit an activated phenotype with limited further proliferative capacity that is restored during recovery.
Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, Cavalli A, Urbani S, Boehme R, Panebianco R, Fiaccadori F, Ferrari C.
Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy.
Hepatology 2001 Apr;33(4):963-71
The hepatitis B virus (HBV) cytotoxic T lymphocyte (CTL) response in patients with chronic HBV infection is generally weak or totally undetectable. This inability to mount protective CTL responses is believed to be a crucial determinant of viral persistence, and its correction represents an important objective of immune therapies for chronic hepatitis B. However, amplification of CTL responses in vivo may be ineffective if HBV-specific CD8 cells are either absent or nonresponsive to exogenous stimulation. In this study, we asked whether antiviral treatments able to inhibit viral replication and to reduce viral and antigen load can successfully reconstitute CTL responses creating the appropriate conditions for their therapeutic stimulation. For this purpose, the HBV-specific CTL response before and during lamivudine therapy was studied longitudinally in 6 HLA-A2-positive patients with HBeAg+ chronic hepatitis B. Both HBV-specific cytotoxic T cell activity measured by chromium release assay on peptide stimulation in vitro and CD8+ T cell frequency measured ex vivo by HLA-A2/peptide tetramer staining were significantly augmented by lamivudine therapy. This enhancement followed the reconstitution of CD4 reactivity and the decline of viral load induced by therapy. Our study shows that lamivudine treatment in chronic hepatitis B can restore CTL reactivity, making CTL susceptible to exogenous stimulation. This effect may enhance the probability that T cell-based immune therapies delivered after lamivudine treatment can successfully reconstitute a protective CTL response able to cure chronic HBV infection.
3)HVB特异性与非特异性免疫不同组合模式决定HBV感染者不同的预后模式
A)HVB特异性免疫合适+非特异性免疫无/低------》健康人隐性HBV感染而自然康复
B)HVB特异性免疫亚合适+非特异性免疫有(TH0、TH1)------》急性肝炎、重症肝炎
C)HVB特异性免疫无+非特异性免疫无------》健康HBV携带者
D)HVB特异性免疫低/无+非特异性免疫有(TH2、TH3)------》慢性肝炎、肝硬化
E)HVB特异性免疫低/无+非特异性免疫低下(NK和NK-T均低下)------》肝癌
Bertoletti A, Maini MK.
Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection?
Curr Opin Microbiol 2000 Aug;3(4):387-92
During infection with hepatitis B or C viruses, cytotoxic T lymphocytes (CTLs) have been implicated as both the mediators of protection and the principal effectors of liver pathology. Recent studies have allowed an investigation of the relationship between virus-specific CTL responses, liver damage and viral replication. In the presence of an efficient virus-specific CTL response, a scenario is emerging where inhibition of viral replication can be independent of liver pathology. We discuss the possibility that an inadequate CTL response--unable to control viral replication--may contribute to liver pathology not only directly but also via the recruitment of non-virus-specific T cells. |
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