Virus infection supports organ acceptance

Chronic hepatitis C virus infections are among the most common reasons for liver transplants. Because existing viruses also infect the new liver, the immune system is highly active there. Despite this, the new organ is not rejected, as scientists from the Helmholtz Zentrum München and the Technische Universität München (TUM) have now discovered. The long-term stimulation of the innate immune system by the virus actually increases the probability of tolerance.

Over 150 million people throughout the world suffer from chronic infection with the hepatitis C virus (HCV), which causes massive damage to the liver. Advanced liver diseases often necessitate liver transplants. In the new clinical study Dr. Felix Bohne and his colleagues studied together with Prof. Alberto Sánchez-Fueyo from King’s College London 34 hepatitis C patients at the Liver Unit of the University Hospital Clínic de Barcelona who had received new livers.

The researchers had two objectives here: first, they wanted to gain a better understanding of the mechanisms that enable the body’s own immune system to tolerate the new organ despite the HCV infection; second, they were looking for factors that could act as biomarkers for tolerance in the patients.

“If tolerance could be reliably predicted based on certain markers, many patients could stop taking immunosuppressants after a certain period of time,” explains Dr. Felix Bohne, lead scientist of the study. Patients must take these strong drugs after transplants. They suppress the immune system so that the body does not identify the new organ as foreign and reject it. For patients with hepatitis C, this is a particular burden, as they need a stable immune system after the transplant to control their chronic HCV infection.

Markers for tolerance
During the study, the patients stopped taking the immunosuppressants. They were observed for twelve months to see which of them could also tolerate the new organ without the drugs, and which of them did not. The scientists took liver and blood samples from the patients prior to and after the cessation of the drugs. Detailed immunological tests on these patient samples were carried out under the leadership of Prof. Ulrike Protzer of the “Immunmonitoring Platform” at the Institute of Virology. The scientists compared the patients with each other and looked for any differences that arose in tolerant patients only.

How is hepatitis C virus spread, is it contagious, and how can transmission be prevented?

HCV is spread (transmitted) most efficiently through exposure to infected blood.

  The most common route of transmission is needles shared among users of illicit drugs.

  Accidental needle-sticks in health care workers also have transmitted the virus. The average risk of getting HCV infection from a stick with a contaminated needle is 1.8% (range 0% to 10%)

  Prior to 1992, some people acquired the HCV infection from transfusions of blood or blood products. Since 1992, all blood products have been screened for HCV, and cases of HCV due to blood transfusion now are extremely rare.

  HCV infection also can be passed from mother to unborn child. Approximately 4 of every 100 infants born to HCV-infected mothers become infected with the virus.

  A small number of cases are transmitted through sexual intercourse. The risk of transmission of HCV from an infected individual to a non-infected spouse or sexual partner without the use of condoms over a lifetime has been estimated to be between 1% and 4%.

  Finally, there have been some outbreaks of HCV when instruments or exposed to blood have been re-used without appropriate cleaning between patients.

And the scientists struck gold: a certain group of genes was very active only in the livers of tolerant patients. The genes in question belonged to the type I interferon system, which targets viruses like HCV as part of the innate immune system. As the results showed, an anti-viral mechanism does actually enable the patients to better tolerate a foreign organ.

Virus infection supports organ acceptance Ulrike Protzer provides a possible explanation for this: “When the interferon system is constantly activated as is the case in some chronically-infected patients, it downregulates other immune reactions in order to protect the body. This state could act like a natural immunosuppressant and reduce the rejection of the organ.”

In addition to the genes of the type I interferon system, a second factor was considered as a possible marker. This was discovered by the researchers in a previous study on liver recipients who did not have a HCV infection. Patients were very likely to be tolerant if they had a certain ratio of two different subgroups of immune cells in their blood. This ratio was also a reliable predictor of tolerance in the new study involving HCV patients.

Dr. Tanja Bauer and Carolina Russo from the Immunmonitoring Platform at the Helmholtz Zentrum München were also involved in the study as cooperation partners. Felix Bohne was awarded a DFG (German Research Foundation) grant for his research work.

Hepatitis C and Liver Transplantation

End-stage liver disease (cirrhosis) due to chronic hepatitis C viral (HCV) infection has become the leading indication for liver transplantation (LTx) in the United States. Unfortunately, LTx does not cure HCV, a common misconception. Instead, recurrent HCV infection of the new liver occurs in almost all instances and some form of liver damage is noted histologically (seen under the microscope in a liver biopsy specimen) in the vast majority of cases.

Furthermore, the natural history of recurrent HCV following LTx appears to be significantly accelerated compared to that in non-LTx cases. Rather than the 20% figure quoted for non-LTx cases who may develop cirrhosis after 20-30 years, anywhere from 10 to 30% of LTx recipients with recurrent HCV have advanced fibrosis (scarring) or full-blown cirrhosis within only 5 years. Another problem is that, once cirrhosis develops post-LTx, complications occur more rapidly than in non-LTx cases. If another LTx is required, the outcome is usually not as favorable and some liver transplant centers refuse to offer a second LTx on this account.

In some instances, a particularly aggressive form of recurrent HCV develops within only a few months post-LTx and this condition has been labelled “fibrosing cholestatic hepatitis” (FCH). It also occurs in some cases of recurrent hepatitis B post-LTx where it was first described. FCH is characterized by progressive jaundice (yellowing of the skin and whites of the eyes) with a rapid decline in liver function leading to liver failure, most often associated with markedly elevated viral levels detected in the bloodstream (more than 20 times pre-LTx levels) and in the liver tissue as well. In these cases, the virus itself appears to be the major cause of liver damage (cytopathic), whereas in most other cases of recurrent HCV post-LTx (as discussed below) the liver damage is thought to be immunologically related, due to “innocent bystander” injury to the liver cells as the immune cells try to kill off the virus, albeit unsuccessfully. In FCH, loss of the new liver is common within 3-6 months post-LTx and retransplantation is invariably a failure. The aggressive nature of FCH suggests that these cases may be infected with a more virulent form of HCV which in some way contributes to the poor outcome, perhaps aggravated by the use of higher doses of immunosuppression early following LTx. Fortunately, this type of recurrent HCV is uncommon.


Thomas Shaw-Stiffel, MD

Original publication
Felix Bohne, María-Carlota Londoño, Carlos Benítez, Rosa Miquel, Marc Martínez-Llordella, Carolina Russo, Cecilia Ortiz, Eliano Bonaccorsi-Riani, Christian Brander, Tanja Bauer, Ulrike Protzer, Elmar Jaeckel, Richard Taubert, Xavier Forns, Miquel Navasa, Marina Berenguer, Antoni Rimola, Juan-José Lozano, und Alberto Sánchez-Fueyo, HCV-induced immune responses influence the development of operational tolerance following liver transplantation in humans, Science Translational Medicine, 2014.
DOI: 10.1126/scitranslmed.3008793

Prof. Dr. Ulrike Protzer
Technische Universität München / Helmholtz Zentrum München
Institute of Virology
Phone: +49 89 4140 - 6821

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