MHH researchers discover molecular signatures that could help with diagnosis.
Discussing the research results (from left): Ahmed Alaswad, Alejandro Campos-Murguia and Dr. Bastian Engel. Copyright: Karin Kaiser/MHH
A liver transplant often saves seriously ill patients. However, there is still a risk that the body will reject the new organ. Physicians differentiate between acute and chronic rejection. While acute rejection is easy to diagnose and treat, chronic rejection causes lasting damage to the organ and is difficult to detect - so far only through tissue samples taken under a microscope. An international research team, led by the Hannover Medical School (MHH) and the Helmholtz Center for Infection Research (HZI), has now discovered clear molecular signatures for chronic rejection after liver transplantation that could help with diagnosis. After ten years of work, the results have now been published in the Journal of Hepatology.
Two types of rejection
"Chronic and acute rejection differ in cause, course and therapy," explains lead author Dr. Bastian Engel, Clinical Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology (GHIE) at MHH. "In chronic rejection, antibodies attack the blood vessels of the transplanted liver, often without abnormal liver values. Up to 50 percent of cases lead to scarring, which can cause liver cirrhosis and make a new transplant necessary." Physicians rely on classic immunosuppressants and measures to reduce antibodies such as plasmapheresis and high-dose immunoglobulin administration for treatment - with varying degrees of success.
Acute rejection is easier to recognize and treat. In this case, immune cells attack the donor liver, which increases the liver values and causes a deterioration in function. The risk of permanent scarring is lower, and acute rejection usually responds well to an adjustment of immunosuppression or temporary high-dose cortisone administration. "The decisive factor is that these two forms not only progress differently, but also show their own molecular activity patterns - typical fingerprints in the organ. We have clearly distinguished these signatures from each other for the first time," explains PhD student and medical assistant Alejandro Campos-Murguia, also first author from the Gastroenterology Clinical Department.
Different treatment - major challenge
For the first time, the team analyzed which genes are active in tissue samples from liver transplant patients with and without acute and chronic rejection. The samples came from Hanover and Barcelona. "We analysed data from gene expression, cytokines, complement factors and the extracellular matrix (ECM) - i.e. various molecules and structures that play a role in cells and tissue - in more than 158 samples," reports Ahmed Alaswad, PhD student at the Centre for Individualised Infection Medicine (CiiM), a joint facility or institutions of the HZI and the MHH, and first author. "Our analyses clearly show for the first time that signaling pathways that lead to liver scarring, such as TNF-NF-κB signaling, and complement activation, part of the innate immune response, are indicative of chronic rejection."
Better diagnosing rejection
The findings are more than just basic research. "In future, these molecular signatures may help to diagnose chronic rejection in surveillance transplant biopsies earlier and more accurately and thus adapt treatment more specifically," says Prof. Dr. Richard Taubert, Senior Physician at the GHIE Liver Transplant Outpatient Clinic.
"The results are an important step towards personalized medicine in transplantation research," emphasizes Prof. Dr. Dr. Yang Li, MHH professor, co-director of CiiM and head of the "Bioinformatics of Individualized Medicine" research department at the HZI. "Our aim is to ensure that every patient receives the best possible individual therapy - so that they can live significantly longer with the transplanted organ."
Text: Camilla Mosel