Biochemical Basis for B Lymphoma Genesis in Organ Transplant Recipients
A major goal of Olivia Martinez's laboratory has been to understand the viral and immune interactions that contribute to the development of post-transplant lymphoproliferative disease (PTLD) in transplant recipients. PTLD is a serious, and often fatal, complication of solid organ and bone marrow transplantation that can manifest as frank B cell lymphomas. Similar lymphomas arise in people with AIDS. Epstein Barr virus (EBV) is the etiologic agent.
In previous studies the Martinez lab has developed molecular techniques to detect and monitor EBV in the circulation of transplant recipients and this approach has been implemented as a routine assay in the clinical management of transplant recipients. The group has determined that EBV B cell lymphomas from patients with PTLD utilize an autocrine IL-10 growth pathway and that this results in constitutive activation of the Jak/STAT signal transduction pathway.
Recently, Martinez and colleagues demonstrated that the immunosuppressive drug rapamycin can significantly inhibit the growth of EBV infected B cells, both in vivo and in vitro. Moreover, rapamycin appears to act through inhibition of IL-10 production and Jak/STAT activation.
We have also demonstrated that transplant recipients have relatively high frequencies of EBV-specific CD8+ T cells in the circulation and that seronegative individuals can generate anti-EBV CTL rapidly following exposure to the virus. However, latent EBV appears to block apoptosis induced through the CTL and NK effector pathways Fas/Fas ligand and TRAIL/DR.
Ongoing studies in the lab are directed towards:
- identifying the viral proteins responsible for modulating apoptosis in EBV infected B cells.
- determining the functional properties of EBV specific CD8 T cells in immunosuppressed patients
- defining the effects on cell cycle proteins that lead to inhibition of proliferation by rapamycin in EBV infected B cells
- determining the effect of the EBV encoded latent membrane protein 1 (LMP1) on Jak/STAT activation and on signal transduction by B cell molecules that, like LMP1, utilize the TRAF family of adaptor proteins.
Trial Administration