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1liver-infiltrating lymphocytes 4 of patients with chronic hepa-A cytotoxic T lymphocyte (CTL) response to the hepatitis C, the role of CTL responses in HCV infection is untitis C virus (HCV) nucleoprotein residues 88-96 that are known. HCV infection frequently persists and is implicated the minimal and optimal epitope for human leukocyte in the development of chronic hepatitis, cirrhosis, and hepatoantigen (HLA) B44-restricted CTLs was assessed in 27 cellular carcinoma. 5 Posttransfusion HCV infection has de-HLA B44-positive patients with chronic HCV infection.creased substantially after introduction of an anti-HCV assay Serum HCV RNA concentration and the amino acid sefor blood screening, but community-acquired HCV infection quence of the residues 81-100 were also determined.still occurs. Interferon therapy is effective in less than 50% Three patients were infected with HCV with uncommon of patients with chronic hepatitis C. 6 Understanding the role amino acid substitutions within the epitope. One was of CTL responses in HCV infection may contribute to the infected with HCV with an amino acid substitution in development of strategies for the prevention of HCV infection the flanking residues of the epitope. To stimulate CTLs and the elimination of HCV from infected individuals. in the peripheral blood, 9-mer peptides that correRecently, we showed the presence of CTLs that recognize sponded to the residues 88-96 of the individual patients endogenously synthesized HCV antigen in the peripheral were synthesized and used. Seven of the 27 patients demblood of some patients with HCV infection by stimulation onstrated a CTL response to the residues 88-96 with of peripheral blood lymphocytes (PBLs) with HCV synthetic specific cytotoxic activities higher than 20%. The CTL peptides.3 activities were significantly higher in patients with a The CTLs recognized an epitope in the HCV nucleoprotein low titer of serum HCV RNA than in those with a high residues 81-100 in association with human leukocyte antigen titer of serum HCV RNA (P Å .0006). Some of the patients (HLA) B44. The minimal and optimal epitope was further dethat demonstrated a CTL response to the residues 88-fined to be the residues 88-96. 7 The 9-mer peptide of the resi-96 also demonstrated a CTL response to a newly identidues 88-96 was recognized by and stimulated the CTLs more fied HLA B44-restricted CTL epitope or a known HLA efficiently than the 20-mer peptide of the residues 81-100. A11-restricted CTL epitope or both. No apparent associa-In a characteristic antiviral CTL response in vivo, immunotion was observed between the CTL response and the dominant CTLs recognize only one or a few multiple immunostage of disease, or between the CTL response and the genic CTL epitopes in the antigen, 8,9 but as many as five grade of necroinflammatory activity. The results suggest different epitopes for HCV-specific CTLs were detected in a that the HLA B44-restricted CTLs together with other single individual. 10 CTL activities to HCV could not be dem-HCV-specific CTLs ...

BackgroundThrombocytopenia represents an obstacle for invasive procedures in chronic liver disease (CLD) patients. We aimed to estimate the appropriate dose and evaluate the efficacy and safety of lusutrombopag for the treatment of thrombocytopenia before percutaneous liver radiofrequency ablation (RFA) for primary hepatic cancer in patients with CLD.MethodsIn this multicenter, randomized, double-blind, placebo-controlled study conducted in Japan, 61 CLD patients with platelet count < 50 × 103/µL at screening were randomized to placebo or lusutrombopag 2, 3, or 4 mg once daily for 7 days, followed by a 28-day post-treatment assessment period. The primary efficacy endpoint was the proportion of patients who did not require platelet transfusion before RFA. The pre-specified key secondary efficacy endpoint was the proportion of responders. Adverse events (AEs) and thrombosis-related AEs were evaluated.ResultsThe proportion of patients who did not require platelet transfusion before RFA and that of responders were significantly higher (p < 0.01) in the 2-mg (80.0, 66.7%), 3-mg (81.3, 68.8%), and 4-mg groups (93.3, 80.0%) compared with the placebo group (20.0, 6.7%) and showed a dose-dependent effect. The incidence of AEs was 97.8 and 100% in the lusutrombopag (all groups) and placebo groups, respectively; no dose-related increase was observed. Four patients experienced thrombosis-related events (one each in the placebo and 2-mg groups, and two in the 4-mg group). A total of 16 (18%) adverse drug reactions occurred in the safety analysis set.ConclusionsLusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count.Clinical trial registrationThe study is registered at JapicCTI-121944.Electronic supplementary materialThe online version of this article (10.1007/s00535-018-1499-2) contains supplementary material, which is available to authorized users.

NK cells are effector lymphocytes playing a critical role in the natural resistance against tumors. However, the precise mechanisms underlying NK cell-mediated natural resistance against tumor metastasis are still unrevealed. B16 cells, mouse melanoma cells, were resistant to freshly isolated NK cell-mediated killing; nevertheless, NK cells were critical for natural resistance against experimental lung metastasis of B16 cells. We found that lung metastasis was increased significantly in IFN-γ(-/-) mice but not pfp(-/-), IFN-αR(-/-), or IL-12/IL-18(-/-) mice. Interestingly, freshly isolated lung NK cells, but not spleen or liver NK cells, displayed augmented IFN-γ production after B16 inoculation. Adoptive transfer of pfp(-/-) NK cells, but not IFN-γ(-/-) NK cells, significantly decreased B16 lung metastasis in IFN-γ(-/-) and pfp/IFN-γ(-/-)mice. Lung metastases of IFN-γRDN B16 was also increased in NK cell-depleted or IFN-γ(-/-) mice, suggesting that the IFN-γ response of host cells was required in the NK cell and IFN-γ-mediated antimetastatic effect. Our results demonstrate that IFN-γ production from lung resident NK cells is a key response in the natural resistance to the experimental lung metastasis of NK cell-resistant tumor cells.

Our results suggest that strong TAA-specific CD8(+) T-cell responses suppress the recurrence of HCC. Immunotherapy to induce TAA-specific cytotoxic T lymphocytes by means such as the use of peptide vaccines should be considered for clinical application in patients with HCC after local therapy.

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