Limits...
Immune response of cytotoxic T lymphocytes and possibility of vaccine development for hepatitis C virus infection.

Hiroishi K, Eguchi J, Ishii S, Hiraide A, Sakaki M, Doi H, Omori R, Imawari M - J. Biomed. Biotechnol. (2010)

Bottom Line: Thus, the development of a vaccine that can induce potent CTL response against HCV is strongly expected.Our findings may contribute to the development of the HCV vaccine.In this paper, we describe the CTL responses in HCV infection and the attempts at vaccine development based on recent scientific articles.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.

ABSTRACT
Immune responses of cytotoxic T lymphocytes (CTLs) are implicated in viral eradication and the pathogenesis of hepatitis C. Weak CTL response against hepatitis C virus (HCV) may lead to a persistent infection. HCV infection impairs the function of HCV-specific CTLs; HCV proteins are thought to actively suppress host immune responses, including CTLs. Induction of a strong HCV-specific CTL response in HCV-infected patients can facilitate complete HCV clearance. Thus, the development of a vaccine that can induce potent CTL response against HCV is strongly expected. We investigated HCV-specific CTL responses by enzyme-linked immuno-spot assay and/or synthetic peptides and identified over 40 novel CTL epitopes in the HCV protein. Our findings may contribute to the development of the HCV vaccine. In this paper, we describe the CTL responses in HCV infection and the attempts at vaccine development based on recent scientific articles.

No MeSH data available.


Related in: MedlinePlus

Destruction of HCV-infected hepatocytes by CTLs. (1) Immature myeloid dendritic cells (iDC) take up hepatitis C virus antigens (HCV Ag) in the liver. (2) The DCs move to a draining lymph node. (3) Matured DCs activate naïve helper T (Th) cells efficiently through stimulation with HLA class II, costimulatory molecules (CD80 and CD86), and cytokines such as IL-12. The stimulated Th cells, in turn, activate DCs by expressing CD40 ligand and secreting TNF-α. IL-12 produced by myeloid DCs differentiates these stimulated Th cells towards Th1 cells. Naïve cytotoxic T lymphocytes (CTLs) recognize the HCV Ag presented on the DCs. IL-2 and IFN-γ secreted by activated Th1 cells induce the activation and proliferation of the HCV-specific CTLs. (4) The stimulated HCV-specific CTLs leave the lymph nodes and move toward the liver. (5) They recognize HCV antigens together with HLA class I on the surface of HCV-infected hepatocytes, and try to eradicate HCV by killing the infected hepatocytes. Abbreviated terms: Th1 cell, type 1 helper T cell; mDC, myeloid dendritic cells; CTL, Cytotoxic T lymphocyte; CD, cluster of differentiation; CD40L, CD40 ligand; TCR, T-cell receptor; HLA, human leukocyte antigen; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2874944&req=5

fig2: Destruction of HCV-infected hepatocytes by CTLs. (1) Immature myeloid dendritic cells (iDC) take up hepatitis C virus antigens (HCV Ag) in the liver. (2) The DCs move to a draining lymph node. (3) Matured DCs activate naïve helper T (Th) cells efficiently through stimulation with HLA class II, costimulatory molecules (CD80 and CD86), and cytokines such as IL-12. The stimulated Th cells, in turn, activate DCs by expressing CD40 ligand and secreting TNF-α. IL-12 produced by myeloid DCs differentiates these stimulated Th cells towards Th1 cells. Naïve cytotoxic T lymphocytes (CTLs) recognize the HCV Ag presented on the DCs. IL-2 and IFN-γ secreted by activated Th1 cells induce the activation and proliferation of the HCV-specific CTLs. (4) The stimulated HCV-specific CTLs leave the lymph nodes and move toward the liver. (5) They recognize HCV antigens together with HLA class I on the surface of HCV-infected hepatocytes, and try to eradicate HCV by killing the infected hepatocytes. Abbreviated terms: Th1 cell, type 1 helper T cell; mDC, myeloid dendritic cells; CTL, Cytotoxic T lymphocyte; CD, cluster of differentiation; CD40L, CD40 ligand; TCR, T-cell receptor; HLA, human leukocyte antigen; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon.

Mentions: The process of HCV-specific CTL induction and the destruction of HCV-infected hepatocytes by CTLs are shown in Figure 2. The destruction of HCV-infected hepatocytes releases HCV fragments; these fragments are taken up by myeloid DCs, consequently activating the DCs. These DCs migrate to the draining lymph nodes and express HCV antigens on human leukocyte antigen (HLA) class II molecules. Then, they enhance expression of costimulatory molecules (CD80, CD86) that interact with and activate antigen-specific helper T (Th) cells [8]. In turn, the activated Th cells promote the maturation of DCs by the expression of CD40 ligand and TNF-α. Subsequently, mature DCs stimulate specific CTLs by antigen presentation on HLA class I molecule and enhance the expression of costimulatory molecules [8]. Cytokines such as IL-2 and IL-12 produced by Th1 cells and DCs further promote CTL activation. These CTLs infiltrate the liver and recognize HCV antigens presented on the surface of HCV-infected hepatocytes together with HLA class I molecules. Then, the effector CTLs release perforin, granzyme, and TNF-α, or express Fas ligand, and initiate a direct attack on HCV-infected hepatocytes [9, 10]. In the previous study, we demonstrated that Fas ligand and TNF-α can also destroy noninfected hepatocytes in the vicinity of the HCV-infected cells [11].


Immune response of cytotoxic T lymphocytes and possibility of vaccine development for hepatitis C virus infection.

Hiroishi K, Eguchi J, Ishii S, Hiraide A, Sakaki M, Doi H, Omori R, Imawari M - J. Biomed. Biotechnol. (2010)

Destruction of HCV-infected hepatocytes by CTLs. (1) Immature myeloid dendritic cells (iDC) take up hepatitis C virus antigens (HCV Ag) in the liver. (2) The DCs move to a draining lymph node. (3) Matured DCs activate naïve helper T (Th) cells efficiently through stimulation with HLA class II, costimulatory molecules (CD80 and CD86), and cytokines such as IL-12. The stimulated Th cells, in turn, activate DCs by expressing CD40 ligand and secreting TNF-α. IL-12 produced by myeloid DCs differentiates these stimulated Th cells towards Th1 cells. Naïve cytotoxic T lymphocytes (CTLs) recognize the HCV Ag presented on the DCs. IL-2 and IFN-γ secreted by activated Th1 cells induce the activation and proliferation of the HCV-specific CTLs. (4) The stimulated HCV-specific CTLs leave the lymph nodes and move toward the liver. (5) They recognize HCV antigens together with HLA class I on the surface of HCV-infected hepatocytes, and try to eradicate HCV by killing the infected hepatocytes. Abbreviated terms: Th1 cell, type 1 helper T cell; mDC, myeloid dendritic cells; CTL, Cytotoxic T lymphocyte; CD, cluster of differentiation; CD40L, CD40 ligand; TCR, T-cell receptor; HLA, human leukocyte antigen; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2874944&req=5

fig2: Destruction of HCV-infected hepatocytes by CTLs. (1) Immature myeloid dendritic cells (iDC) take up hepatitis C virus antigens (HCV Ag) in the liver. (2) The DCs move to a draining lymph node. (3) Matured DCs activate naïve helper T (Th) cells efficiently through stimulation with HLA class II, costimulatory molecules (CD80 and CD86), and cytokines such as IL-12. The stimulated Th cells, in turn, activate DCs by expressing CD40 ligand and secreting TNF-α. IL-12 produced by myeloid DCs differentiates these stimulated Th cells towards Th1 cells. Naïve cytotoxic T lymphocytes (CTLs) recognize the HCV Ag presented on the DCs. IL-2 and IFN-γ secreted by activated Th1 cells induce the activation and proliferation of the HCV-specific CTLs. (4) The stimulated HCV-specific CTLs leave the lymph nodes and move toward the liver. (5) They recognize HCV antigens together with HLA class I on the surface of HCV-infected hepatocytes, and try to eradicate HCV by killing the infected hepatocytes. Abbreviated terms: Th1 cell, type 1 helper T cell; mDC, myeloid dendritic cells; CTL, Cytotoxic T lymphocyte; CD, cluster of differentiation; CD40L, CD40 ligand; TCR, T-cell receptor; HLA, human leukocyte antigen; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon.
Mentions: The process of HCV-specific CTL induction and the destruction of HCV-infected hepatocytes by CTLs are shown in Figure 2. The destruction of HCV-infected hepatocytes releases HCV fragments; these fragments are taken up by myeloid DCs, consequently activating the DCs. These DCs migrate to the draining lymph nodes and express HCV antigens on human leukocyte antigen (HLA) class II molecules. Then, they enhance expression of costimulatory molecules (CD80, CD86) that interact with and activate antigen-specific helper T (Th) cells [8]. In turn, the activated Th cells promote the maturation of DCs by the expression of CD40 ligand and TNF-α. Subsequently, mature DCs stimulate specific CTLs by antigen presentation on HLA class I molecule and enhance the expression of costimulatory molecules [8]. Cytokines such as IL-2 and IL-12 produced by Th1 cells and DCs further promote CTL activation. These CTLs infiltrate the liver and recognize HCV antigens presented on the surface of HCV-infected hepatocytes together with HLA class I molecules. Then, the effector CTLs release perforin, granzyme, and TNF-α, or express Fas ligand, and initiate a direct attack on HCV-infected hepatocytes [9, 10]. In the previous study, we demonstrated that Fas ligand and TNF-α can also destroy noninfected hepatocytes in the vicinity of the HCV-infected cells [11].

Bottom Line: Thus, the development of a vaccine that can induce potent CTL response against HCV is strongly expected.Our findings may contribute to the development of the HCV vaccine.In this paper, we describe the CTL responses in HCV infection and the attempts at vaccine development based on recent scientific articles.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.

ABSTRACT
Immune responses of cytotoxic T lymphocytes (CTLs) are implicated in viral eradication and the pathogenesis of hepatitis C. Weak CTL response against hepatitis C virus (HCV) may lead to a persistent infection. HCV infection impairs the function of HCV-specific CTLs; HCV proteins are thought to actively suppress host immune responses, including CTLs. Induction of a strong HCV-specific CTL response in HCV-infected patients can facilitate complete HCV clearance. Thus, the development of a vaccine that can induce potent CTL response against HCV is strongly expected. We investigated HCV-specific CTL responses by enzyme-linked immuno-spot assay and/or synthetic peptides and identified over 40 novel CTL epitopes in the HCV protein. Our findings may contribute to the development of the HCV vaccine. In this paper, we describe the CTL responses in HCV infection and the attempts at vaccine development based on recent scientific articles.

No MeSH data available.


Related in: MedlinePlus