Severe West Nile virus meningoencephalitis in a pediatric renal transplant recipient: successful recovery and long-term neuropsychological outcome.

West Nile Virus is an arbovirus that has rapidly spread throughout the United States since the first case was described in Queens, New York in 1999. There has been increasing reports of both community-acquired and organ-derived infections in renal transplant recipients. In immunocompromised individuals, WNV infection is a life-threatening disease with significant neurological morbidity. We report the only pediatric case of community-acquired WNV disease in a renal transplant recipient to undergo detailed long-term neuropsychological assessment. Increased surveillance and prompt treatment of WNV meningoencephalitis is critical, and our report highlights the effectiveness of immunosuppression reduction without compromising allograft outcomes.

Syk-induced phosphatidylinositol-3-kinase activation in Epstein-Barr virus posttransplant lymphoproliferative disorder.

Posttransplant lymphoproliferative disorder (PTLD)-associated Epstein-Barr virus (EBV)+ B cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B cell receptor (BCR) mimic, provides survival signals to virally infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV-associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol-3'-kinase (PI3K)/Akt signaling in EBV+ B cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV-infected B cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib-treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV-associated malignancies.

Activation of the JAK/STAT pathway in Epstein Barr virus+-associated posttransplant lymphoproliferative disease: role of interferon-gamma.

Epstein Barr virus (EBV) is associated with B-cell lymphomas in posttransplant lymphoproliferative disease (PTLD). Latent membrane protein 1 (LMP1), the major oncogenic protein of EBV, promotes tumorigenesis through activation of NF-kappaB, Erk, p38, JNK and Akt. The Jak/STAT signal transduction pathway is also constitutively active in PTLD-associated EBV(+) B-cell lymphomas. Here we determine the mechanism of Jak/STAT activation in EBV(+) B-cell lymphomas and the role of LMP1 in this process. Immunoprecipitation studies revealed no direct interaction of LMP1 and JAK3, but known associations between JAK3 and common gamma chain, and between LMP1 and TRAF3, were readily detected in EBV(+) B cell lines from patients with PTLD. An inducible LMP1 molecule expressed in EBV(-) BL41 Burkitt's cells demonstrated STAT activation only after prolonged LMP1 signaling. While LMP1 induced IFN-gamma production in BL41 cells, IFN-gamma receptor blockade and IFN-gamma neutralization prior to LMP1 activation markedly decreased STAT1 activation and expression of LMP1-driven IFN-gamma inducible genes. Understanding the mechanisms by which EBV induces cellular signal transduction pathways may facilitate development of new treatments for PTLD.

Idiotype-encoding recombinant adenoviruses provide protective immunity against murine B-cell lymphomas.

Vaccination with tumor-specific immunoglobulin or idiotype (Id) is a promising new form of immunotherapy for B-cell malignancies. Id protein vaccination has demonstrated clinical activity in B-cell lymphomas, yet it requires the laborious and time-consuming procedures of tumor-myeloma cell hybridization, large-scale in vitro culture, and protein purification. Recombinant adenoviruses are highly efficient and immunogenic gene transfer vehicles from which individualized vaccines can be rapidly assembled using polymerase chain reaction-amplified tumor Id genes. Id-encoding adenoviruses were evaluated as vaccines in 2 murine B-cell lymphoma models. A single injection of recombinant Id adenovirus provided protection from subsequent tumor challenge that was equivalent or superior to that afforded by Id protein vaccination. Protected mice had substantial serum titers of Id-specific antibodies. When used in conjunction with chemotherapy, vaccination also prolonged the survival of mice bearing pre-existing tumor. Mechanistic studies demonstrated that tumor protection was not dependent upon T cells. Importantly, in mice prevaccinated with an irrelevant adenovirus, tumor protection following vaccination with Id adenovirus was not significantly impaired. These findings have implications for the design of future lymphoma immunotherapy trials.