Role of Kupffer Cell and NK Cell Interactions in Hepatitis C Virus Infektion
Final Report Abstract
In the current grant we studied the interaction of liver resident Kupffer cells and intrahepatic Natural Killer (NK) cells in the context of hepatitis C virus (HCV) replication in vitro using the HCV replicon system. Although we found that intrahepatic lymphocytes (IHL) in general exert a greater antiviral effect than peripheral blood lymphocytes (PBL), we were not able to show that this translates to differences in production of the antiviral cytokine INFγ, nor to increased cytotoxicity by intrahepatic NK cells. Because of this unexpected finding and since introduction of all-oral direct acting antiviral (DAA) treatment has revolutionized care of patients with chronic HCV infection, basic research in the field of HCV infection suddenly became less important to the medical research community; therefore, we did not continue to pursue the in vitro part of this grant and rather focused on the translational patient studies. In patients, we showed that DAA treatment primarily affected subsets within the blood monocyte, NK cell and memory T cell compartments: knowing only pretreatment frequencies of these subsets allowed accurate classification of 83% of patients as “fast” (HCV RNA negative by 4 weeks) or “slow” (HCV RNA positive at 4 weeks) responders. This discovery opens the possibility of identifying individuals prior to DAA treatment who may not require a full 12-week course, which might lead to better optimised resource allocation. Furthermore, we asked whether chronic HCV-infected liver transplant (LTx) recipients also have polarized NK cell function and investigated whether elimination of the virus by sofosbuvir-based DAAs and addition of RBV could improve NK cell function. Compared to the uninfected LTx recipients, NK cells from chronic HCV-infected LTx recipients were polarized towards cytotoxicity with increased CD107a degranulation and reduced capacity to produce IFNγ. Successful DAA therapy did not affect CD107a degranulation, but decreased STAT-1. RBV co-treatment with DAA therapy for HCV increased CD56Bright NK cell IFNg responses in LTx recipients and this correlated to an increase in pSTAT-4. This is relevant especially for immunocompromised patients such as LTx recipients or patients with end-stage liver disease.
Publications
- Immune Reconstitution After HCV Clearance With Direct Antiviral Agents: Potential Consequences for Patients With HCC? Transplantation. 2017 May;101(5):904-909
Werner JM, Adenugba A, Protzer U
(See online at https://doi.org/10.1097/TP.0000000000001606) - Predicting Early Viral Control under Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus Using Pretreatment Immunological Markers. Front. Immunol., 2018 Feb 7;9:146
Hutchinson JA, Weigand K, Adenugba A, Kronenberg K, Haarer J, Zeman F, Riquelme P, Hornung M, Ahrens N, Schlitt HJ, Geissler EK and Werner JM
(See online at https://doi.org/10.3389/fimmu.2018.00146) - International SiLVER study group. HCC recurrence in HCV patients after liver transplantation: SiLVER Study reveals benefits of sirolimus in combination with CNIs. Transpl Int. 2020 Apr 21
Werner JM, Hornung M, Krah R, Götz M, Schnitzbauer AA, Schlitt HJ and Geissler EK
(See online at https://doi.org/10.1111/tri.13621)
