J A Trapani

..Several other potential tumor escape mechanisms that can block the cytotoxic pathways activated by killer T cells have also been proposed...

..Future studies of serpins may bring insights into how cells that synthesize granzymes are protected from inadvertent cell suicide...

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..Entry of granzyme B into target cells and its intracellular trafficking to induce target cell death in the presence of perforin are therefore not critically dependent on MPR or clathrin/dynamin-dependent endocytosis...

..The recent discovery of a triply mutated human granzyme B allele, whose product is predicted to possess a reduced capacity to induce cell death, opens the way for major progress in these areas in coming years...

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..This functional dissociation of cytochrome c and SMAC release from loss of DeltaPsim demonstrates the essential contribution of Bid upstream of caspase activation during granzyme B-induced apoptosis...

..Overall, our results indicate that mitochondrial perturbation by Bid is necessary to achieve a lethal threshold of caspase activity and cell death due to granzyme B...

..These experiments define the transcriptional mechanisms of IFI 16 gene regulation and provide evidence suggesting that AP-1 activation may be an important event in IFN signaling...

..This defines a therapeutic window in which ABT-737 and CL synergise to cause maximum death of cancer cells that are resistant to either treatment alone, which will be essential in defining optimum treatment regimens...

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..This study confirms CD8(+) LeY-T cells have a CM- and EM-like phenotype and heterogeneous function consistent with potential to persist in vivo after adoptive transfer...

..Here we will discuss the mechanisms by which these stellar killers achieve their goal...

..Consequently, we plan to use T cells manufactured under Good Manufacturing Practice conditions in a phase I immunotherapy study for patients with Le(Y)-positive myeloma or AML...

..These findings demonstrate a possible link between gene induction following interferon stimulation and p53-mediated cellular events...

..Thus, filamin is a functionally important substrate for granzyme B, as its cleavage may account at least partly for caspase-independent cell death mediated by the granzyme...

..This review explains the current model of IFN action, during viral infections and the potential for well-established and emerging groups of IFN inducible genes as therapeutic targets is highlighted...

..These data indicate that perforin, and hence direct cytotoxicity, plays a key role in the ability of adoptively transferred CD8+ cytotoxic T lymphocytes to eradicate established xenografts...

..Here, Joseph Trapani and colleagues argue that CTL cytolytic granules are the principal apoptotic means of eliminating viruses and possess multiple independent mechanisms to counter the viral anti-apoptotic machinery...

..We conclude that cell death in response to perforin and granzyme B does not require caspase activation and still proceeds efficiently through non-nuclear pathways when nuclear substrate cleavage is inhibited...

..The fate of such a cell therefore reflects the balance of pro-apoptotic (immune) and anti-apoptotic (viral) strategies that have developed over eons of evolutionary time...

..Finally, IFI 16 isoforms can homo- and heterodimerize, and we have mapped the dimerization domain to the amino terminus which contains an imperfect leucine zipper domain...

..Rather, a perforin-dependent signal results in a redistribution of grB from the cytoplasm to the nucleus, where it may contribute to the nuclear changes associated with apoptosis...

..This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide...

..This series of experiments has revealed the utility of scFv anti-CEA chimeras in providing mouse T cells the capacity to reject colon carcinoma in an Ag- and perforin-specific manner...

..Thus, IFI 16 is a transcriptional repressor, with a modular structure typical of many known transcription regulators...

..The significance of the cytotoxic and importantly the non-cytotoxic roles of Grz will be discussed in this review, detailing accepted and controversial functions...

..This review discusses the pathological manifestations of CL deficiencies due to impaired perforin function and describes novel aspects of perforin biology...

..In vitro apoptosis of Sézary cells was demonstrated in one patient following exogenous bexarotene. CONCLUSIONS: Apoptosis is not detectable in the circulation of patients with Sézary syndrome treated with bexarotene...

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..This study indicates that the use of retroviral vectors to transduce T cells does not lead to malignant transformation...

..These findings have rejuvenated interest in the immunosurveillance of tumors, and recent data have provided evidence that the immune system influences the development of some spontaneous epithelial malignancies...

..The findings described below suggest that TGF-beta and its signaling pathways will be major targets for novel cancer therapeutics...

..This study supports the use of humanized gene-modified T cells as a potential therapy for Le(Y+) malignancies...

..In this study, we discuss our recent findings on granzyme B-induced cell death and discuss the potential relevance of this pathway to CL-induced death of viral-infected and transformed cells...

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..Therefore, CTLs from granzyme AB(-/-) mice induce target cell death by a unique mechanism that is distinct from both perforin lysis and apoptosis...

..Our data suggest that Bid cleavage by granzyme B precedes mitochondrial disruption and apoptosis in pancreatic islets...

..We conclude that cathepsin B is not essential for protection of cytotoxic lymphocytes from the toxic effects of their secreted perforin...

..Therefore, NOD8.3 T-cells use both perforin and Fas pathways to kill beta-cells and the surprising blockade of NOD8.3 T-cell-mediated beta-cell death by SOCS-1 overexpression may be due in part to reduced target cell recognition...

..These results demonstrate that even "orthologous" granzymes have species-specific functions, having evolved in distinct environments that pose different challenges...

..This clinical picture has prompted further work to uncover the molecular structure of perforin and to define its precise role in immune regulation and immunopathology...

..These findings provide the first direct evidence that hPRF-A91V is functionally abnormal and provides a rationale for why it may be responsible for disordered immune homeostasis if inherited with another dysfunctional perforin allele...

..Unlike the protease, the extended granzyme B recognition and cleavage site in Bid, a key pro-apoptotic substrate, was invariant...

..This chapter discusses the significance of human perforin polymorphisms, particularly those associated with diseases other than FHL, and recent advances in our understanding of perforin biology and function...

..These data support the use of gene-modified CD4(+) Th1 and CD8(+) T cells for mediating a sustained antitumor response...

..This suggests that grzK plays an important role in CD8(+) T-cell cytotoxicity both in the presence and absence of grzA and B...

..However, in the absence of perforin, the Fas/FasL pathway provides an alternative mechanism dependent on islet cell Fas upregulation by cytokines IFNgamma and TNFalpha...

..In this electrostatic "exchange-adsorption" model, cs1 and cs2 participate in binding of GrB to the cell surface, thereby promoting its uptake and eventual release into the cytoplasm...

..These data raise the likelihood that granzyme M represents a third major and specialized perforin-dependent cell death pathway that plays a significant role in death mediated by NK cells...

..We conclude that the RAH allele represents a neutral polymorphism in the GrB gene...

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..Our study has illustrated the practical advantage of engineering a T-cell signaling complex that codelivers CD28 activation, dependent only upon the tumor's expression of the appropriate tumor associated antigen...

..A significant incidence of late onset adenocarcinoma observed in both IFN-gamma- and pfp-deficient mice indicated that some epithelial tissues were also subject to immunosurveillance...

..These results taken together demonstrate that PI 3-kinase may control NK lytic function via granule polarization towards the contacted target cell...

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..The finding that granzyme H is frequently more abundant than granzyme B in NK cells is consistent with a role for granzyme H in complementing the pro-apoptotic function of granzyme B in human NK cells...

..One of the most potent of these toxins is the serine protease granzyme B. This review will discuss mechanisms used by granzyme B to enter target cells and the ways in which it synergizes with other granule toxins to cause cell death...

..Unlike wild type cells, Bid-deficient cells survived and were then able to proliferate normally, demonstrating the critical role for Bid in mediating granzyme B-induced apoptosis...

..This report represents the first systematic functional analysis of HLH-associated missense mutations and the 2 most common perforin polymorphisms...

..This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure-function relationships for lymphocyte perforin...

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..T cell adjuvant treatment of day 8 metastatic disease resulted in dramatic increases in survival of mice, and this survival was significantly greater than that afforded by either doxorubicin, 5-fluorouracil, or herceptin...

..Overall, this study has highlighted the therapeutic potential of using combined transfer of antigen-specific gene-modified CD8+ and CD4+ T cells to significantly enhance T-cell adoptive transfer strategies for cancer therapy...

..Cathepsin C deficiency also results in considerably milder immune deficiency than perforin or granzyme A/B deficiency...

..More than 80 delegates from 20 countries attended the conference, which was held in the convivial surroundings of the Novotel Resort at Palm Cove, north Queensland...

..It may also contribute to tissue destruction in diseases in which extracellular GrB is evident, such as rheumatoid arthritis and atherosclerosis...

..This article addresses recent key advances in genetic, clinical and biochemical studies that have reignited the current interest in perforin biology...

..We conclude that GrB nuclear import exhibits complex regulation by IMPs; that heterodimerization with PI-9 can modulate the interaction has implications for protection against apoptosis...

..Together with biochemical studies, these structural data suggest that lytic MACPF proteins use a CDC-like mechanism of membrane disruption, and will help understand the roles these proteins play in immunity and development...

..Thus, p202 plays a role in regulating the proliferative capacity of hematopoietic cells...

..Finally, after experimentally verifying an optimized three-dimensional model, we have made predictions on the impact of two inherited perforin mutations of the C2 domain on calcium-dependent lipid binding and cell lysis...

..This Review describes recent progress in defining the structure, function, biochemistry and cell biology of perforin...

..In this chapter, we highlight separation of cytosolic and mitochondrial fractions of cultured cells using digitonin as the method for measuring cytochrome c release that, in our hands has been the simplest and most reproducible...

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..Sequence similarity between bacterial and vertebrate MACPF domains suggests that the fold of the CDCs, a family of proteins important for bacterial pathogenesis, is probably used by vertebrates for defense against infection...

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..These data indicate that external signals can alter lymphocyte polarization toward antigen-presenting cells or target cells, inhibiting lymphocyte function...

..As cell death mediated through TNF-superfamily members and their respective receptors is covered elsewhere, this manuscript will deal specifically with cytotoxic granule-mediated cell death...