Strategies for management of EBV and adenovirus infections after allogeneic stem cell transplantation

Sammanfattning: Viral infections are one of the challenges that can threaten successful allogeneic HSCT especially during the period of immune reconstitution resulting in a high mortality risk. Adenoviruses and EBV are important viruses during this period. Adenovirus infections can cause invasive adenovirus disease and EBV can cause post transplant lymphoproliferative disease (PTLD). Both are associated with significant morbidity and mortality if they are not discovered early and preemptive treatments are not given. IL-7 is a non-redundant cytokine that has important functions in T-cell survival, proliferation and memory formation. It is a growth factor for pre B-cells. It may have a role to improve T cell reconstitution early after HSCT. The aim of the thesis was to develop strategies to prevent severe viral complications after allogeneic HSCT. In the adenovirus part, we aimed to study the predictive value of adenoviremia for the development of adenovirus disease and to examine a surveillance strategy to control adenovirus disease. In the EBV-PTLD part, we aimed to see the effect of prospective monitoring of EBV load on PTLD control and to study the role of IL-7/IL-7R on PTLD development. We characterized in paper I adenovirus infections in a Swedish adult cohort after allogeneic HSCT. We found that incidence of adenoviremia was 4.9% in the studied population. CMV and EBV infections may occur to a large extent in patients with adenoviremia. Most patients with positive adenovirus PCR had sustained adenoviremia. Preemptive treatment with cidofovir might be a good treatment option to control adenoviremia. In study II we examined a surveillance strategy to control adenovirus infections. We found that only 5% of the patients had adenoviremia, no one developed adenovirus disease, or required antiviral treatment. This surveillance strategy could be applied to children and high risk adults. Most adult patients had adenovirus specific Tcell immune response in the first three months after allogeneic HSCT. A monitoring strategy of patients at a high risk of EBV-PTLD was applied. The effect of the strategy was compared with results of a historical control group in whom the strategy was not applied. We showed that 5.6% of high risk patients in the study group developed PTLD and 1.9% died from PTLD with the corresponding numbers in the control group being 9.4 and 5.7% for development of PTLD and death due to PTLD, respectively. Splenectomy was found to be a high risk factor in the study group. This monitoring strategy was able to face the high risk factors and can be applied safely. In study IV we found reduced responsiveness of IL-7 by the STAT5 phosphorylation assay in both CD4+ and CD8+ T-cells in PTLD patients. However, the reduced responsiveness of IL-7 was found only in CD8+ T-cells in the control group. IL-7R was found to be more expressed in PTLD patients than controls and was found to be expressed on other immune cells. This functional dysfunction in IL-7/IL-7R may help to identify and monitor patients at a high risk of EBV-PTLD. In conclusion, surveillance strategy to monitor high risk patients can help to reduce severe virological complications. Monitoring of IL-7 function might be a predictor of EBV-PTLD.