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Cytotoxic Molecules (cytotoxic + molecule)
Selected AbstractsReactive oxygen and nitrogen species in normal physiological processesACTA PHYSIOLOGICA, Issue 1 2010J. Pourova Abstract Reactive oxygen species (ROS) and reactive nitrogen species have generally been considered as being highly reactive and cytotoxic molecules. Besides their noxious effects, ROS participate in physiological processes in a carefully regulated manner. By way of example, microbicidal ROS are produced in professional phagocytes, ROS function as short-lived messengers having a role in signal transduction and, among other processes, participate in the synthesis of the iodothyronine hormones, reproduction, apoptosis and necrosis. Because of their ability to mediate a crosstalk between key molecules, their role might be dual (at least in some cases). The levels of ROS increase from a certain age, being associated with various diseases typical of senescence. The aim of this review is to summarize the recent findings on the physiological role of ROS. Other issues addressed are an increase in ROS levels during ageing, and the possibility of the physiological nature of this process. [source] Extracellular ATP, P2 receptors, and inflammationDRUG DEVELOPMENT RESEARCH, Issue 1 2003Francesco Di Virgilio Abstract Over the past few years, P2 receptors have emerged as new potential players in the early phases of inflammation in their function of chemotactic receptors, triggers of proinflammatory cytokine release, and cytotoxic molecules. However, more recent data suggest that the role of P2 receptors in immunity is much more widespread and touches the very heart of the initiation of the immune response, i.e., antigen presentation by dendritic cells. Drug Dev. Res. 59:171,174, 2003. © 2003 Wiley-Liss, Inc. [source] Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2006Gennadiy Zelinskyy Abstract Cytolytic CD8+ T cells are critical for the control of acute Friend virus (FV) infection yet they fail to completely eliminate the virus during chronic infection because they are functionally impaired by regulatory T cells (Treg). We performed a kinetic analysis of T cell responses during FV infection to determine when dysfunction of CD8+ T cells and suppressive activity of CD4+ regulatory T cells develops. At 1,week post infection, virus-specific CD8+ T cells with effector phenotype and cytolytic potential expanded. Peak expansion was found at 12,days post infection, correlating with peak viral loads. After 2,weeks when viral loads dropped, numbers of activated CD8+ T cells started to decline. However, a population of virus-specific CD8+ T cells with effector phenotype was still detectable subsequently, but these cells had lost their ability to produce granzymes and to degranulate cytotoxic molecules. Contemporaneous with the development of CD8+ T cell dysfunction, different CD4+ T cell populations expressing cell surface markers for Treg and the Treg-associated transcription factor Foxp3 expanded. Transfer as well as depletion experiments indicated that regulatory CD4+ cells developed during the second week of FV infection and subsequently suppressed CD8+ T cell functions, which was associated with impaired virus clearance. [source] Natural killer cell cytotoxicity: how do they pull the trigger?IMMUNOLOGY, Issue 1 2009Nicola J. Topham Summary Natural killer (NK) cells target and kill aberrant cells, such as virally infected and tumorigenic cells. Killing is mediated by cytotoxic molecules which are stored within secretory lysosomes, a specialized exocytic organelle found in NK cells. Target cell recognition induces the formation of a lytic immunological synapse between the NK cell and its target. The polarized exocytosis of secretory lysosomes is then activated and these organelles release their cytotoxic contents at the lytic synapse, specifically killing the target cell. The essential role that secretory lysosome exocytosis plays in the cytotoxic function of NK cells is highlighted by immune disorders that are caused by the mutation of critical components of the exocytic machinery. This review will discuss recent studies on the molecular basis for NK cell secretory lysosome exocytosis and the immunological consequences of defects in the exocytic machinery. [source] Mechanisms of regulatory T-cell suppression , a diverse arsenal for a moving targetIMMUNOLOGY, Issue 1 2008Dorothy K. Sojka Summary Naturally-occurring regulatory T cells (Tregs) are emerging as key regulators of immune responses to self-tissues and infectious agents. Insight has been gained into the cell types and the cellular events that are regulated by Tregs. Indeed, Tregs have been implicated in the control of initial activation events, proliferation, differentiation and effector function. However, the mechanisms by which Tregs disable their cellular targets are not well understood. Here we review recent advances in the identification of distinct mechanisms of Treg action and of signals that enable cellular targets to escape regulation. Roles for inhibitory cytokines, cytotoxic molecules, modulators of cAMP and cytokine competition have all been demonstrated. The growing number of inhibitory mechanisms ascribed to Tregs suggests that Tregs take a multi-pronged approach to immune regulation. It is likely that the relative importance of each inhibitory mechanism is context dependent and modulated by the inflammatory milieu and the magnitude of the immune response. In addition, the target cell may be differentially susceptible or resistant to distinct Treg mechanisms depending on their activation or functional status at the time of the Treg encounter. Understanding when and where each suppressive tool is most effective will help to fine tune therapeutic strategies to promote or constrain specific arms of Treg suppression. [source] Listeriolysin O as cytotoxic component of an immunotoxinPROTEIN SCIENCE, Issue 6 2009Sabine Bergelt Abstract Monoclonal antibodies (mAbs) have been developed over the past years as promising anticancer therapeutics. The conjugation of tumor specific mAbs with cytotoxic molecules has been shown to improve their efficacy dramatically. These bifunctional immunotoxins, consisting of covalently linked antibodies and protein toxins, possess considerable potential in cancer therapy. Many of them are under investigation in clinical trials. As a result of general interest in new toxic components, we describe here the suitability of the bacterial protein Listeriolysin O (LLO) as cytotoxic component of an immunotoxin. Unique characteristics of LLO, such as its acidic pH optimum and the possibility to regulate the cytolytic activity by cysteine-oxidation, make LLO an interesting toxophore. Oxidized LLO shows a substantially decreased cytolytic activity when compared with the reduced protein as analyzed by hemolysis. Both oxidized and reduced LLO exhibit a cell-type-unspecific toxicity in cell culture with a significantly higher toxicity of reduced LLO. For cell-type-specific targeting of LLO to tumor cells, LLO was coupled to the dsFv fragment of the monoclonal antibody B3, which recognizes the tumor-antigen Lewis Y. The coupling of LLO to dsFv-B3 was performed via cysteine-containing polyionic fusion peptides that act as a specific heterodimerization motif. The novel immunotoxin B3-LLO could be shown to specifically eliminate antigen positive MCF7 cells with an EC50 value of 2.3 nM, whereas antigen negative cell lines were 80- to 250-fold less sensitive towards B3-LLO. [source] Microglia as immune effectors of the central nervous system: Expression of cytokines and chemokinesCLINICAL AND EXPERIMENTAL NEUROIMMUNOLOGY, Issue 2 2010Seung U. Kim Abstract Microglia, one of three glial cell types in the central nervous system (CNS), play an important role as resident immunocompetent and phagocytic cells in the CNS in the event of injury and disease. It was del Rio Hortega in 1927 who determined that microglia belong to a distinct glial cell type in the CNS, apart from astrocytes and oligodendrocytes. Since the 1970s, there has been wide recognition that microglia are immune effectors in the CNS that respond to pathological conditions and participate in the initiation and progression of neurological disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis and acquired immune deficiency syndrome dementia complex by releasing potentially cytotoxic molecules such as pro-inflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins. There is also evidence to suggest that the microglia are capable of secreting neurotrophic or neuron survival factors on activation through inflammation or injury. In the present review, the current status of knowledge on biology and immunology of microglia is reported. (Clin. Exp. Neuroimmunol. doi: 10.1111/j.1759-1961.2010.00007.x, 2010) [source] | ||||||||||