Journal of leukocyte biology
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Adoptive immunotherapy can induce dramatic tumor regressions in patients with melanoma or viral-induced malignancies, but extending this approach to many common cancers has been hampered by a lack of naturally occurring tumor-specific T cells. In this review, we describe recent advances in the genetic modification of T cells using genes encoding cell-surface receptors specific for tumor-associated antigen. Using genetic modification, the many functional properties of T cells, including cytokine secretion and cytolytic capacity, are redirected from their endogenous specificity toward the elimination of tumor cells. Advances in gene design, vectors, and cell production are discussed, and details of the progress in clinical application of this approach are provided.
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PDE4 inhibitors are effective anti-inflammatory drugs whose effects and putative mechanisms on resolution of inflammation and neutrophil apoptosis in vivo are still unclear. Here, we examined the effects of specific PDE4 inhibition on the resolution of neutrophilic inflammation in the pleural cavity of LPS-challenged mice. LPS induced neutrophil recruitment that was increased at 4 h, peaked at 8-24 h, and declined thereafter. ⋯ LPS resulted in a time-dependent activation of Akt, which was blocked by treatment with rolipram or PI3K and Akt inhibitors, and PI3K and Akt inhibitors also enhanced apoptosis and promoted neutrophil clearance. Although LPS induced NF-kappaB activation, which was blocked by rolipram, NF-kappaB inhibitors did not promote resolution of neutrophil accumulation in this model. In conclusion, our data show that PDE4 inhibition resolves neutrophilic inflammation by promoting caspase-dependent apoptosis of inflammatory cells by targeting a PKA/PI3K/Akt-dependent survival pathway.
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The decreased production of antimicrobial peptides in tissues surrounding the burn sites has been described in patients with severe burn injury. Small numbers of Pseudomonas aeruginosa spread easily to the whole body of burn mice when infected at burn site tissues. Gr-1(+)CD11b(+) cells, demonstrated in tissues surrounding the burn site, are inhibitory on the production of antimicrobial peptides by EK. ⋯ However, Gr-1(+)CD11b(+) cells, which were treated previously with glycyrrhizin, did not produce these soluble factors. Also, sepsis stemming from P. aeruginosa burn-site infection was not demonstrated in burn mice treated with glycyrrhizin. These results suggest that through the improved production of antimicrobial peptides in tissues surrounding the burn area, sepsis stemming from P. aeruginosa wound infection is controllable by glycyrrhizin in severely burned mice.