Immune-regulation of human cytomegalovirus in the immunocompromised host
Hematological stem cell transplantation (HSCT) is one of the most important treatments for haematological malignancies. Two major complications after stem cell transplantations are the development of graft-versus-host disease (GvHD) and the reactivation of the human cytomegalovirus (HCMV), which occurs in 60% of seropositive patients. This reactivation can have severe consequences, leading, for example, to pneumonitis, colitis or encephalitis and increasing the patients’ morbidity and mortality.
The aim of this project is to find new host and viral factors, or biomarkers, which allow us to predict HCMV reactivation and outcome after stem cell transplantation. This has the potential to facilitate the use of individual therapies with fewer side effects for the patient, thereby improving quality of life and survival after HSCT.
Major complications after HSCT include the development of GvHD and the reactivation of HCMV, which can cause severe diseases such as pneumonia, colitis or encephalitis. In about 60% of HCMV seropositive patients (either recipient or donor positive), HCMV reactivates after HSCT. Thus, the virus is still the major infectious complication 30 - 100 days after stem cell transplantation, causing increased morbidity and mortality. Prophylactic antiviral treatment is generally not suitable for HCMV seropositive HSCT patients due to severe side effects of antiviral drugs such as ganciclovir on the hematopoietic system.
While some factors are already known to influence reactivation of HCMV in transplant patients, viral genes and proteins and their influences on the modulation of the host’s cytokine secretion have not yet been studied in detail. Additionally, differences in viral strains or genome populations could play a role in the outcome of HCMV reactivation after stem cell transplantation. Therefore, the aim of this study is to determine cellular as well as viral factors that could serve as predictors of HCMV reactivation and indicate how the outcome after HSCT can be improved. Furthermore, this study can also give more detailed insights into the effect of cytokine profiles on the development of GvHD after HSCT. Ultimately, reliable biomarkers would make it possible to individually treat the patients according to their personal risk of developing HCMV disease or GvHD.
This study is based at the Hannover Medical School. It is coordinated by Dr. Penelope Kay-Fedorov (Institute of Virology) in cooperation with Prof. Dr. Eva Mischak-Weissinger from the Institute of Hematology, Hemostasis, Oncology and Stem cell Transplantation, from which patients are recruited and Prof. Dr. Christine S. Falk from the Institute of Transplant Immunology, who provides Luminex quantitative cytokine measurements. Dr. Tina Ganzenmüller and PD. Dr. Albert Heim, both from the Institute of Virology, support the project with their expertise in clinical virology and next generation sequencing, helping to determine viral genes that could have an influence on immune reconstitution, HCMV reactivation and outcome after HSCT.
To define biomarkers, clinical parameters such as CMV reactivation or GvHD will be compared with plasma cytokine levels at different time points after HSCT (up to day 100 post HSCT), CMV serostatus, CMV strain and the degree of immune reconstitution.
Preliminary data already indicate that cytokine secretion differs between CMV reactivating and CMV non-reactivating patients and that a combination of factors e.g. cytokines could serve as risk biomarkers for the prediction of CMV reactivation of HSCT patients. Furthermore, sequencing data suggest that differences in CMV strains could have an influence on the development of GvHD after HSCT.
In the future we will continue to recruit patients, using the DZIF transplant cohort to access other centres, in order to extend and validate these results.
