Anti-CD137 mAb Deletes Both Donor CD4+ and CD8+ T Cells in Acute Graft-versus-host Disease

We previously demonstrated that in vivo engagement of CD137, a member of TNF receptor superfamily, can delete allorective CD4+ T cells through the induction of activation-induced cell death (AICD) in chronic graft-versus-host disease (cGVHD) and subsequently reverse established cGVHD. In this study, we further showed that agonistic anti-CD137 mAb was highly effective in triggering AICD of donor CD8+ T cells as well as donor CD4+ T cells in the C57BL/6→unirradiated (C57BL/6 × DBA/2)F1 acute GVHD model. Our results suggest that strong allostimulation should facilitate AICD of both alloreactive CD4+ and CD8+ T cells induced by CD137 stimulation. Therefore, depletion of pathogenic T cells using agonistic anti-CD137 mAb combined with potent TCR stimulation may be used to block autoimmune or inflammatory diseases mediated by T cells

Drug delivery by a self-assembled DNA tetrahedron for overcoming drug resistance in breast cancer cells

A DNA tetrahedron is employed for efficient delivery of doxorubicin into drug-resistant breast cancer cells. The drug delivered with the DNA nanoconstruct is considerably cytotoxic, whereas free doxorubicin is virtually non-cytotoxic for the drug-resistant cells. Thus, the DNA tetrahedron, made of the inherently natural and biocompatible material, can be a good candidate for the drug carrier to overcome MDR in cancer cells.close11

Titanium dioxide induces apoptotic cell death through reactive oxygen species-mediated Fas upregulation and Bax activation

Background: Titanium dioxide (TiO2) has been widely used in many areas, including biomedicine, cosmetics, and environmental engineering. Recently, it has become evident that some TiO2 particles have a considerable cytotoxic effect in normal human cells. However, the molecular basis for the cytotoxicity of TiO2 has yet to be defined.Methods and results: In this study, we demonstrated that combined treatment with TiO2 nanoparticles sized less than 100 nm and ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-dependent upregulation of Fas and conformational activation of Bax in normal human cells. Treatment with P25 TiO2 nanoparticles with a hydrodynamic size distribution centered around 70 nm (TiO2P25-70) together with ultraviolet A irradiation-induced caspase-dependent apoptotic cell death, accompanied by transcriptional upregulation of the death receptor, Fas, and conformational activation of Bax. In line with these results, knockdown of either Fas or Bax with specific siRNA significantly inhibited TiO2-induced apoptotic cell death. Moreover, inhibition of reactive oxygen species with an antioxidant, N-acetyl-L-cysteine, clearly suppressed upregulation of Fas, conformational activation of Bax, and subsequent apoptotic cell death in response to combination treatment using TiO2P25-70 and ultraviolet A irradiation.Conclusion: These results indicate that sub-100 nm sized TiO2 treatment under ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-mediated upregulation of the death receptor, Fas, and activation of the preapoptotic protein, Bax. Elucidating the molecular mechanisms by which nanosized particles induce activation of cell death signaling pathways would be critical for the development of prevention strategies to minimize the cytotoxicity of nanomaterials.This work was supported by the Korea Ministry of Environment and The Eco-Technopia 21 Project (091-091-081)

Identification of gp96 as a Novel Target for Treatment of Autoimmune Disease in Mice

Heat shock proteins have been implicated as endogenous activators for dendritic cells (DCs). Chronic expression of heat shock protein gp96 on cell surfaces induces significant DC activations and systemic lupus erythematosus (SLE)-like phenotypes in mice. However, its potential as a therapeutic target against SLE remains to be evaluated. In this work, we conducted chemical approach to determine whether SLE-like phenotypes can be compromised by controlling surface translocation of gp96. From screening of chemical library, we identified a compound that binds and suppresses surface presentation of gp96 by facilitating its oligomerization and retrograde transport to endoplasmic reticulum. In vivo administration of this compound reduced maturation of DCs, populations of antigen presenting cells, and activated B and T cells. The chemical treatment also alleviated the SLE-associated symptoms such as glomerulonephritis, proteinuria, and accumulation of anti-nuclear and –DNA antibodies in the SLE model mice resulting from chronic surface exposure of gp96. These results suggest that surface translocation of gp96 can be chemically controlled and gp96 as a potential therapeutic target to treat autoimmune disease like SLE

Huge carotid body paraganglioma

A 33-year-old woman was admitted to our hospital with a slow-growing mass in the left side of her neck. The mass was found to be a huge (73 × 56 × 54 mm) carotid body paraganglioma. Another 21 mm-size tumor was incidentally detected at the right carotid bifurcation. She had hoarseness and Horner's syndrome of her left side. Both tumors were surgically removed. There were no cerebrovascular complications but some neurologic complications occurred when the left tumor was removed

Improved Surgical Technique for Heterotopic Aortic Transplantation in Mice

Transplant arteriosclerosis is the main limitation for long-term survival of solid organ transplant recipients. Animal models would provide invaluable tools to investigate the cellular and molecular mechanisms underlying the pathogenesis of transplant arteriosclerosis, as well as for studies with novel drugs and other reagents for the prevention of the disease. We have therefore developed a modified technique for aortic transplantation in mice. The central suture ligation of the recipient abdominal aorta allowed a simpler end-to-side anastomosis of a segment of the donor thoracic aorta into the infrarenal portion of the recipient abdominal aorta. Using this technique, the overall survival rate was 94%. We also observed typical aspects of chronic rejection of the aortic allografts not observed with isografts. Our new technique is relatively easy to perform and has a low incidence of thrombosis, thus being useful for studying various aspects of transplant arteriosclerosis