Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver.
This study aimed to assess serum human telomerase enzyme (hTERT) levels and their relation to the progression of liver disease. Also, it aimed to assess the effect of hepatitis C virus (HCV) core protein on memory T-cells in HCV patients with or without HCC and the correlation between memory cell phenotype and the progression of the disease in the same patients.
HTERT level in serum was assessed through relative quantitative RT-PCR. Flow cytometric analysis was used to assess T-cell responsiveness (as IFN- γ secretion) before and after stimulation with HCV core protein and the memory CD8+ cell phenotype using several differentiation markers.
HTERT was found to be increased in a stepwise manner upon comparing its level in controls, chronic hepatitis patients, cirrhotic patients, and HCC patients. T-cells showed a similar manner of stepwise decrease in response (decreased IFN- γ secretion) in HCC patients compared to HCV patients without HCC and controls. Also, late differentiated memory cells (CD8+, CD27-, CD28-, CD45RA+, and CCR7-) were depleted in HCC patients compared to HCV patients without HCC.
These results suggest a negative correlation between hTERT and IFN- γ secretion by T-cells in HCV patients and that this relationship, along with the depletion of late differentiated memory cells, could help the progression of liver disease to HCC.
© 2023 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. This study aimed to assess serum hTERT level and its relation to the progression of liver disease. Also, it aimed to assess the effect of HCV core protein on memory T-cells in HCV patients with or without HCC, and the correlation between memory cells phenotype and the progression of the disease in the same patients. hTERT level in serum was assessed through relative quantitative RT-PCR. Flow cytometric analysis was used to assess T-cells responsiveness (as IFN-γ secretion) before and after stimulation with HCV core protein, and memory CD8+ cells phenotype using several differentiation markers. hTERT was found to be increased in a stepwise manner upon comparing its level in controls, chronic hepatitis patients, cirrhotic patients, and HCC patients. T-cells showed a similar manner of stepwise decrease in response (decreased IFN-γ secretion) in HCC patients compared to HCV patients without HCC and controls. Also, late differentiated memory cells (CD8+ CD27- CD28- CD45RA+CCR7-) were depleted in HCC patients compared to HCV patients without HCC. In conclusion, these results suggest a negative correlation between hTERT and IFN-γ secretion by T- cells in HCV patients and that this relationship along with the depletion of late differentiated memory cells could help the progression of liver disease to HCC.

Preventing xenograft rejection is one of the greatest challenges of transplantation medicine. Here, we describe a reproducible, long-term survival of cardiac xenografts from alpha 1-3 galactosyltransferase gene knockout pigs, which express human complement regulatory protein CD46 and human thrombomodulin (GTKO.hCD46.hTBM), that were transplanted into baboons. Our immunomodulatory drug regimen includes induction with anti-thymocyte globulin and αCD20 antibody, followed by maintenance with mycophenolate mofetil and an intensively dosed αCD40 (2C10R4) antibody. Median (298 days) and longest (945 days) graft survival in five consecutive recipients using this regimen is significantly prolonged over our recently established survival benchmarks (180 and 500 days, respectively). Remarkably, the reduction of αCD40 antibody dose on day 100 or after 1 year resulted in recrudescence of anti-pig antibody and graft failure. In conclusion, genetic modifications (GTKO.hCD46.hTBM) combined with the treatment regimen tested here consistently prevent humoral rejection and systemic coagulation pathway dysregulation, sustaining long-term cardiac xenograft survival beyond 900 days.

By ligating CD80/CD86 (B7) molecules, the synthetic immunomodulatory reagent CTLA4-Ig (soluble synthetic CTLA4 fusion protein) induces expression of the enzyme indoleamine 2,3-dioxygenase (IDO) in some dendritic cells (DCs), which acquire potent T cell regulatory functions as a consequence. Here we show that this response occurred exclusively in a population of splenic DCs co-expressing the marker CD19. B7 ligation induced activation of the transcription factor signal transducer and activator of transcription (STAT1) in sorted CD19+, but not CD19(NEG), DCs. STAT1 activation occurred even when DCs lacked receptors for type II IFN (IFNgamma); however, STAT1 activation and IDO up-regulation were not observed when DCs lacked receptors for type I IFN (IFNalphabeta). Thus, IFNalpha, but not IFNgamma, signaling was essential for STAT1 activation and IDO up-regulation in CD19+ DCs following B7 ligation. Consistent with these findings, B7 ligation also induced sorted CD19+, but not CD19(NEG), DCs to express IFNalpha. Moreover, recombinant IFNalpha induced CD19+, but not CD19(NEG), DCs to mediate IDO-dependent T cell suppression, showing that IFNalpha signaling could substitute for upstream signals from B7. These data reveal that a minor population of splenic DCs expressing the CD19 marker is uniquely responsive to B7 ligation, and that IFNalpha-mediated STAT1 activation is an essential intermediary signaling pathway that promotes IDO induction in these DCs. Thus, CD19+ DCs may be a target for regulatory T cells expressing surface CTLA4, and may suppress T cell responses via induction of IDO.