Immunological reviews
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Immunological reviews · Jul 2014
ReviewDirecting traffic: IL-17 and IL-22 coordinate pulmonary immune defense.
Respiratory infections and diseases are among the leading causes of death worldwide, and effective treatments probably require manipulating the inflammatory response to pathogenic microbes or allergens. Here, we review mechanisms controlling the production and functions of interleukin-17 (IL-17) and IL-22, cytokines that direct several aspects of lung immunity. Innate lymphocytes (γδ T cells, natural killer cells, innate lymphoid cells) are the major source of IL-17 and IL-22 during acute infections, while CD4(+) T-helper 17 (Th17) cells contribute to vaccine-induced immunity. ⋯ Recent studies found that stimulation of macrophages and DCs with IL-17 also contributes to antibacterial immunity, while IL-22 promotes epithelial proliferation and repair following injury. Chronic diseases such as asthma and chronic obstructive pulmonary disease have been associated with IL-17 and IL-22 responses directed against innocuous antigens. Future studies will evaluate the therapeutic efficacy of targeting the IL-17/IL-22 pathway in pulmonary inflammation.
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Immunological reviews · Jan 2014
ReviewOf CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma.
Adoptive T-cell therapy recently achieved impressive efficacy in early phase trials, in particular in hematologic malignancies, strongly supporting the notion that the immune system can control cancer. A current strategy of favor is based on ex vivo-engineered patient T cells, which are redirected by a chimeric antigen receptor (CAR) and recognize a predefined target by an antibody-derived binding domain. Such CAR T cells can substantially reduce the tumor burden as long as the targeted antigen is present on the cancer cells. ⋯ This article reviews a recently described strategy for overcoming this shortcoming of the CAR T-cell therapy by modulating the tumor stroma by a CAR T-cell-secreted transgenic cytokine like interleukin-12 (IL-12). The basic process is that CAR T cells, when activated by their CAR, deposit IL-12 in the targeted tumor lesion, which in turn attracts an innate immune cell response toward those cancer cells that are invisible to CAR T cells. Such TRUCKs, T cells redirected for universal cytokine-mediated killing, exhibited remarkable efficacy against solid tumors with diverse cancer cell phenotypes, suggesting their evaluation in clinical trials.
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Immunological reviews · Sep 2011
ReviewMolecular mechanisms of inflammasome activation during microbial infections.
The innate immune system plays a crucial role in the rapid recognition and elimination of invading microbes. Detection of microbes relies on germ-line encoded pattern recognition receptors (PRRs) that recognize essential bacterial molecules, so-called pathogen-associated molecular patterns (PAMPs). A subset of PRRs, belonging to the NOD-like receptor (NLR) and the PYHIN protein families, detects viral and bacterial pathogens in the cytosol of host cells and induces the assembly of a multi-protein signaling platform called the inflammasome. ⋯ Here, we discuss latest advances and our insights on inflammasome stimulation by two model intracellular pathogens, Francisella tularensis and Salmonella typhimurium. Recent studies on these pathogens have significantly shaped our understanding of the molecular mechanisms of inflammasome activation and how microbes can evade or manipulate inflammasome activity. In addition, we review the role of the inflammasome adapter ASC in caspase-1 autoproteolysis and new insights into the structure of the inflammasome complex.
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Inflammasomes are multi-protein complexes that sense microbial molecules and endogenous danger signals in intracellular compartments. Inflammasome assembly results in caspase-1 activation, which in turn drives maturation and secretion of the pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18, and induces pyroptosis to eliminate the infectious agent. The importance of inflammasomes in regulating immune responses was recognized with the discovery of polymorphisms in genes encoding inflammasome components and their linkage to aberrant production of IL-1β and IL-18 in autoimmune and hereditary periodic fevers syndromes. We review the current knowledge on the role of inflammasomes in regulating innate and adaptive immune responses with an emphasis on the role of these immune complexes in autoinflammatory disorders and autoimmune diseases such as colitis, type I diabetes, multiple sclerosis and vitiligo.
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The NLRP3 inflammasome is activated in response to a variety of signals that are indicative of damage to the host including tissue damage, metabolic stress, and infection. Upon activation, the NLRP3 inflammasome serves as a platform for activation of the cysteine protease caspase-1, which leads to the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Dysregulated NLRP3 inflammasome activation is associated with both heritable and acquired inflammatory diseases. Here, we review new insights into the mechanism of NLRP3 inflammasome activation and its role in disease pathogenesis.