Human monocytes and neutrophils play major roles in clearing bacteria from human blood and tissues. We found that the herpes virus entry mediator (HVEM) was highly expressed in monocytes and neutrophils, and its interaction with "homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM/tumor necrosis factor (TNF)-related 2" (LIGHT) enhanced bactericidal activity against Listeria monocytogenes and Staphylococcus aureus. The LIGHT-HVEM interaction increased levels of phagocytosis, interleukin (IL)-8, TNF-alpha, nitric oxide (NO), and reactive oxygen species (ROS) in monocytes and neutrophils. Anti-HVEM monoclonal antibody was able to block LIGHT-induced bactericidal activity, cytokine production (IL-8 and TNF-alpha), and ROS generation. Moreover, inhibition of ROS and NO production blocked LIGHT-induced bactericidal activity. Our results indicate that the LIGHT/HVEM interaction in monocytes and neutrophils contributes to antibacterial activity.
4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily, is a T-cell-costimulatory receptor that is expressed on activated T cells, dendritic cells, and NK cells. Little has been reported about its role in early host defense against bacterial infection. In this study, we report that 4-1BB-deficient (4-1BB ؊/؊ ) mice are much more susceptible to Listeria monocytogenes (intracellular bacteria) infections than wild-type mice. Upon L. monocytogenes infection, 4-1BB ؊/؊ mice showed a lower survival rate, a higher bacterial burden in organs, and larger hepatic microabscesses than 4-1BB ؉/؉ mice. 4-1BB ؊/؊ mice also had impairment in clearance of bacteria from the bloodstream. Neutrophils from 4-1BB ؉/؉ mice constitutively expressed 4-1BB, which could be activated to induce intracellular Ca 2؉ influx by ligation with anti-4-1BB antibody. On the other hand, neutrophils from 4-1BB ؊/؊ mice were defective in reactive oxygen species generation, phagocytic activities, and intracellular Ca 2؉ mobilization. In addition, mice pretreated with anti-4-1BB monoclonal antibody were much more resistant to L. monocytogenes infection than control antibody-treated mice. Our results support the notion that 4-1BB may play a major role in host defense against intracellular pathogens through neutrophil activation.
Renal cell carcinoma (RCC), one of the most incurable malignancies, is highly resistant to chemotherapy and radiotherapy. Cytokine immunotherapy has been the standard approach, but the overall response rate is still very low. Administration of agonistic anti-4-1BB monoclonal antibody (mAb) has been shown to induce regression of several animal tumors but its effect on RCC is unknown. We show here that monotherapy with either anti-4-1BB mAb or the cytotoxic drug, 5-fluorouracil (5-FU), has little effect on established RCC, Renca tumors, but combination therapy with anti-4-1BB mAb and 5-FU eradicates the tumors in more than 70 % of mice. The regressing tumor tissues from mice receiving the combination therapy contained more apoptotic tumor cells and tumor infiltrating lymphocytes than tumor tissues from mice receiving 5-FU or anti-4-1BB mAb monotherapy. The number of lymphocytes in the spleens and tumor-draining lymph nodes (TDLNs) of the combination therapy mice was greatly increased compared to that of control or 5-FU monotherapy mice. Mice that had recovered due to the combination therapy rapidly rejected rechallenge with the tumor, pointing to the establishment of long-lasting tumor-specific memory. Our results indicate that targeting tumors with 5-FU, and immune cells with 4-1BB stimulation, could be a useful strategy for treating incurable RCC. ' 2008 Wiley-Liss, Inc.Key words: 5-FU; anti-4-1BB mAb; combined therapy; renal cell carcinoma Renal cell carcinoma (RCC) is highly metastatic and generally resistant to radiotherapy, chemotherapy and other systemic therapies. For example, 5-FU and related compounds produce an objective response rate of only 5%. Cytokine immunotherapy using interferon-a or IL-2 gives better responses and has now become the mainstay systemic treatment for RCC. However, even cytokine immunotherapy is still limited by toxic side effects and low response rates (11-19%).
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