Nadal
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Infektiologie, Abteilung » Prof. Dr. David Nadal » Nadal
Completed research project
| Title / Titel | Central nervous system Epstein-Barr virus-positive post-transplant lymphoproliferative disorders in children – mechanisms of resistance to corticosteroid treatment | ||
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| Abstract (PDF, 14 KB) | |||
| Summary / Zusammenfassung | Almost all human individuals experience infection with the Epstein-Barr virus (EBV) which subsequently persists in the B-cell pool of the host for a life-time. EBV has the capacity to induce post-transplant lymphoproliferative disorder (PTLD), a serious major and unfortunately unresolved complication of organ transplantation. Children are especially prone to PTLD given the age-related high frequency of primary EBV infection. Moreover, primary EBV infection in the immunosuppressed is burdened with an increased risk for PTLD due to impaired immune responses. Corticosteroids may efficiently halt and abolish EBV-induced lymphoproliferation, but the distinct responses of PTLD to corticosteroid treatment and the relation to the localization of PTLD within or outside the central nervous system (CNS) are poorly understood. Considering that CNS PTLD exhibits a significantly worse prognosis versus non-CNS PTLD and that children are at highest risk for PTLD, an improved understanding of the mechanisms impacting on the emergence of EBV-positive CNS PTLD and its susceptibility to corticosteroid treatment is highly desirable, especially for children. Here we propose to investigate our hypothesis that EBV-induced PTLD within the CNS is more resistant to corticosteroid treatment than PTLD outside the CNS. To study the mechanisms involved, we will generate and characterize EBV-induced lymphoblastoid cell lines (LCL) to mimic PTLD and its variation of responses to corticosteroid treatment in vitro and in vivo. For the in vivo studies we will use NOD/SCID-mice xenotransplanted with LCLs into the CNS and outside the CNS (intra-peritoneal) as a model for CNS PTLD versus non-CNS PTLD, respectively. Moreover, corticosteroid-resistant and corticosteroid-susceptible PTLD will be generated in vitro and tested in vivo. The differences between CNS vs. non-CNS PTLD, as well as the differences between corsicosteroid resistant vs. susceptible will be measured by proteome analysis to identify candidate proteins. We will compare these results to the signatures obtained from pediatric PTLD patients aiming at identifying and characterizing the specific cellular and viral proteins which are involved in the pathogenesis of pediatric CNS PTLD, and uncover the mechanism of corticosteroid resistance. Elucidation of the pathogenic mechanisms will open up the field for improved individual risk assessment and the engineering of more effective novel treatments or even prophylactic modalities against a pediatric CNS which incidence can be predicted to rise with increasing numbers of transplants. |
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| Keywords / Suchbegriffe | EBV, central nervous system | ||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Foundation |
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| Duration of Project / Projektdauer | Jun 2008 to May 2010 |