Development of novel therapies of hematologic malignancies based on the functional modulation of the OX40/gp34 system

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Role of TRAF3 in OX40 signalingWe previously reported that OX40 signaling leads to NF-κB activation via TRAF2 and TRAF5. TRAF3 also binds to the cytoplasmic domain of OX40 but functiions rather negatively to suppress NF-κB activation. In the present study we found that overexpression of TRAF3 did not affect NIK- or IKKα-medicated NF-κB activation and that both N-terminus and C-terminus deletion mutants of TRAF3 have inhibitory effect. These results indicate that TRAF3 suppresses NF-κB activation at the pathway between TRAF2 and NIK, which is not necessarily due to competitive inhibition of binding between OX40 and TRAF2.gp34 expressed on endothelial cells provides T cells with costimulatory signalsPurified normal human CD4+ T cells did not proliferate in response to immobilized anti-CD3 mAb but showed vigorous proliferation in the coexistence of human umbilical vein endothelial cells (HUVEC). Addition of anti-gp34 mAb maredly inhibited this response, indicating that the OX40/gp34 syste … More m plays a major role in costimulation of CD4+ T cells by endothelial cells.Correlation of peripheral blood OX40+ T cells with chronic graft-versus-host disease (cGVHD)We studied whether the expression of OX40 is related to the development of cGVHD in patients who underwent allogeneic hematopoietic stem cell transplant. Peripheral blood mononuclear cells from a total of 22 patients after day 100 were subjected to multi-color flow cytometry. The percentages of both OX40+CD4+ and OX40+CD8+ T cells were significantly higher in patients with cGVHD than those without Serial analyses showed that OX40+CD4+ T cells elevated before the onset of cGVHD and at the onset closely correlated with the therapeutic response. These results indicated that serial measurement of OX40+ T cells is quite useful for predicting the onset as well as therapeutic response of cGVHD.Possible role of the OX40/gp34 in the leukemogenesis of ATLWe studied the relationship between OX40 signals and apoptosis of ATL cells. ATL constitutively express OX40 and became resistant to anti-Fas-induced apoptosis when cocultured MMCE-gp34 while coculture with MMCE-mock had no effects. Thus, it is suggested that ATL cells receive favorable signals for survival through the OX40/gp34 system.Signaling of gp34 induces vascular endothelial cells to produce RANTESWe searched for genes that were induced or upregulated by gp34 signaling in HUVECs to define its downstream biological events. HUVECs expressing high levels of gp34 were stimulated with recombinant soluble OX40 or mock control and subjected to analysis using cDNA expression arrays. We found that a CC chemokine RANTES is one of such inducible genes. Namely, gp34 signaling induces expression of RANTES at both mRNA and protein levels in HUVECs and suggest a possible link between the OX40/gp34 system and RANTES during the process of T cell adhension to endothelial cells and subsequent extravasation. Less