immunologic cytotoxicity

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..These data demonstrated for the first time a bidirectional cross talk between NK cells and DC, in which NK cells activated by IL-2 or by mature DC induce DC maturation...

..Cumulatively, the data presented here demonstrate that CD107a is a sensitive marker of NK cell activity...

..The ability of CTLs to kill intracellular M. tuberculosis was dependent on the presence of granulysin in cytotoxic granules, defining a mechanism by which T cells directly contribute to immunity against intracellular pathogens...

..Resting NK cells also stimulated autologous DC maturation in a TNF-alpha/contact-dependent manner, however, increasing the NK/DC ratio only led to an enhancement of this effect...

..These results raise the possibility that an induced expression of MICA/B, by conditions that may be related to tumor homeostasis and growth, could play a role in immune responses against tumors...

..Moreover, we show that NKp30 is encoded by the previously identified 1C7 gene, for which the function and the cellular distribution of the putative product were not identified in previous studies...

..These findings indicate how NKp46-expressing NK cells may recognize target cells infected by influenza or parainfluenza without the decreased expression of target-cell MHC class I protein...

..In conclusion, this study reports the first characterization of the molecular structure of a NK-specific receptor involved in the mechanism of NK cell activation during natural cytotoxicity...

..New insights into the migration of NK cells, their activation status and production of matrix-degrading proteases might help to overcome this localization defect, with implications for the treatment of human cancer...

..Thus, the present results justify the design of larger follow-up studies to assess the clinical response to DC vaccines loaded with killed allogeneic tumor cells in patients with metastatic melanoma...

..Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction...

..abstract truncated at 400 words)..

..Thus, the granule secretory pathway plays an unexpected role in inflammation, with GzmA acting as an endogenous modulator...

..Finally, we demonstrate that indoleamine 2,3-dioxygenase and prostaglandin E2 represent key mediators of the MSC-induced inhibition of NK cells...

..Our data suggest that the involvement of NKG2D in natural killer cell-mediated cytotoxicity strictly correlates with the expression and the surface density of MICA and ULBP on target cell tumors of different histotypes...

..Thus, the oligoclonal T cell repertoire against an immunodominant persistent viral epitope is established early in primary infection by the rapid selection of public clonotypes, rather than being a stochastic process...

..So, an understanding of the mechanisms that are used by CTLs to destroy targets and a knowledge of pathogen immune-evasion strategies will provide vital information for the design of new therapies...

..This cytotoxicity is dependent on CD18 adhesive interactions but is independent of Fas/FasL. Our findings suggest that the perforin/granzyme pathway is one of the mechanisms that Treg cells can use to control immune responses...

..Herein is a report on the experience of clinical-scale, good manufacturing practices (GMPs) production of NK cells to treat advanced cancer...

..These findings provide a novel insight into the mechanisms evolved by HIV-1 to escape from the NK-cell response...

..Altogether, these findings strongly suggest that NCR are responsible for the killing of autologous APC through the activation of PI-3 K...

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..In this study, we demonstrate CD4-dependent MHC class II-restricted killing in lymphocytic choriomeningitis virus-infected mice in vivo using an in vivo cytotoxicity assay that features class II-expressing B cells as targets...

..These findings strongly support the concept that a cytotoxic effector-memory CD8(+) T cell population operates in vivo to control this persistent viral infection...

..Therefore, strategies to block inhibitory receptors may be of potential use in increasing the efficacy of immunotherapy. (Blood. 2001;97:3132-3137)..

..e. in the frequency, phenotype and function or quality of T cells, are the causes or effects - or both - of the variation in the efficiency of virus control...

..In this model of experimental influenza infection, IFN-gamma is not necessary for the development of an effective humoral or cellular immune response to challenge with this respiratory virus...

..Both the unique cellular distribution and functional capability of p46 molecules suggest a possible role in the mechanisms of non-major histocompatibility complex-restricted cytolysis mediated by human NK cells...

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..These results suggest that subpopulations of CTL and NK cells may be uniquely suited for combating HIV...

..The proliferation of CD16(+) CD56(bright) NK cells was also induced when PBMC were stimulated with penicillin-treated Streptococcus pyogenes, thus suggesting their role in tumour immunity and bacterial infections...

..This high homology together with the presence of a charged amino acid (Arg) in the transmembrane portion suggest that MAR-1 may associate at the cell membrane into a multimeric complex with ITAM containing polypeptides...

..These data show that CTLs use a previously unreported mechanism for delivering secretory granules to the immunological synapse, with granule secretion controlled by centrosome delivery to the plasma membrane...

..The priority is now to demonstrate that immunization against some of these antigens is clinically valuable for antitumor therapy, and the first results of clinical pilot studies are now emerging...

..The prognostic value of NCR expression is discussed, and pathophysiologic implication of the NCR phenotype will be further investigated in a larger study...

..These data imply that the inhibitory function of p58 is dependent on its tyrosine phosphorylation and on recruitment and activation of HCP...

..Resting splenic natural killer cell activity was reduced in IFN-gamma-deficient mice. Thus, IFN-gamma is essential for the function of several cell types of the murine immune system...

..This principle should be considered in designing clinical trials involving adoptive transfer-based immunotherapy of human malignancies...

..We suggest that DCs are able to control directly the expansion of NK cells and that the lysis of immature DCs can regulate the afferent limb of innate and adaptive immunity...

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..These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses...

..In addition, we will discuss other cell-surface receptors expressed differentially by human NK-cell subsets and the distinct functional properties of these subsets...

..We conclude that GrM targets major components of the cytoskeleton that likely contribute to NK cell-induced cell death...

..These disorders highlight the determinant role of this lytic pathway in the control of lymphocyte expansion and homeostasis. New effectors of this secretory pathway have been thus identified...

..These findings should help optimizing the ex-vivo generation of large numbers of cytotoxic effector cells for immunotherapy...

..Moreover, our data indicate that death receptor-mediated apoptosis has a more prominent role in the clearance of NK-sensitive tumors than previously suggested...

..direct activation of caspase-3/-7 by granzyme B or Apo2L/TRAIL, and restores their susceptibility to immunologic cytotoxicity. These findings identify an important mechanism by which cancers evade elimination by immune effector ..

..In this review we will briefly summarize the current understanding of general NK cell biology, and then present the knowledge obtained thus far in the bovine species...

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..The intracellular sequestration of NKG2D ligands by UL16 represents a novel HCMV immune evasion mechanism to add to the well-documented viral strategies directed against antigen presentation by classical MHC molecules...

..Thus, although Ly49-mediated inhibitory signals can prevent many types of effector responses, they do not globally inhibit cellular function, but rather the inhibitory signal is spatially restricted towards resistant targets...

..In addition to their participation in the immediate innate immune response against infection, interactions between NK cells and dendritic cells shape the nature of the subsequent adaptive immune response to pathogens...

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..In contrast, NKG2D costimulates activated CD8(+) T cells. Thus, NKG2D engagement directly stimulates NK cells and macrophages, costimulates CD8(+) T cells, and plays a substantial role in natural killing...

..T-bet and Eomes, thus, ensure that CD8+ T cells adopt an appropriate course of intracellular rather than extracellular destruction...

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..This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation...

..Thus, certain tumours may escape FasL-dependent immune-cytotoxic attack by expressing a decoy receptor that blocks FasL...

..The poor cytolytic capacity of CD56bright NK cells can be explained by weak ability in forming conjugates with target cells and low contents of perforin and granzyme A in their granules...

..We think that the recognition and killing of target cells by NK cells represents an important pathway for the generation of robust CD8+ T and humoral responses that may be exploited for vaccine development...

..We here describe a role for V alpha14 iNKT cells in modulating conventional T-cell responses to antigen expressed in liver, using transferrin-mOVA (Tf-mOVA) mice...

..These results demonstrate that PLCgamma2 is crucial for development of the NK cell receptor repertoire and signaling of activating NK cell receptors, mediating optimal NK cell function in vivo...

..Furthermore, the efficacy of autologous Ag-loaded DC vaccines may well be enhanced by IL-12 overexpression and loading with alphaGC...

..This rapid generation of allospecific CTL activity during a viral infection preceded the peak of viral epitope-specific T cell responses, as detected by in vivo or in vitro cytotoxicity assays...

..Thus, dissociation between delivery system and adjuvant would provide a more flexible and reliable system to induce potent and protective CTL...

..Their unique ability to lyse tumor cells, present Ags, and secrete inflammatory cytokines suggests that NKDC may play a crucial role in linking innate and adaptive immunity...

..However, increasing the leukemia-reactive precursor frequency to a clinically exploitable level will be the key for the design of successful T-cell therapy trials...

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..Notably, adoptive transfer of MCMV-activated CD11b(+) DCs resulted in improved control of MCMV infection, indicating that these cells participate in controlling viral replication in vivo...

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..Our results suggest that high concentrations of either IL-2 or IL-15 will activate the lytic capacity and granzyme B expression of many T cells and that antigen recognition is not required...

..Thus, NF-kappaB activation signaling through ITAM receptors is regulated by a cell type-specific mechanism depending on the usage of adaptors CARMA1 and CARD9, which determines the PKC dependence of the signaling...

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..Overall, these results have revealed that CD40L-DC could activate an innate immune reaction by stimulating NK cells followed by carcinoma cells, supporting that administration of CD40L-DC may have potential as an anticancer therapy...

..Targeting iNKT cells to the tumor site thus may activate a combined innate and adaptive immune response that may prove to be effective in cancer immunotherapy...

..These results show a critical role for OX40L on DCs, via binding to OX40 on NKT cells and CD4+ T cells, in the induction of antitumor immunity in tumor-bearing mice...

..Moreover, our recent findings suggest that SHPS-1 on DCs is also essential for the priming of CD4+ T cells by DCs...

..Our data suggest that HLA-E-restricted CTL may represent an additional effector cell type involved in defenses against HCMV, a virus which escapes the control exerted by conventional CTL or NK cells...

..Thus, by specifically bridging NK cells and myeloid cells, NKp80-AICL interactions may contribute to the initiation and maintenance of immune responses at sites of inflammation...

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..Thus, NK cells rather than NKT cells may be a crucial early activated killer induced by alpha-GalCer in vivo...

..Collectively, our results indicate that NK cells are required during the priming of cytotoxic T-cell response by DC-based tumor vaccine and seem to delineate a mechanism by which DC vaccine can provide the desired immunity...

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..These studies demonstrate the complexity of L. monocytogenes-mediated tumor immunotherapy targeting the human tumor Ag, HPV-16 E7...

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..Taken together, these data illustrate the crucial role played by KLRG1 during the termination of mouse NK cell activation...

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..Coordinated regulation of B7 costimulation and TAP-dependent cross-presentation results in priming of Ag-specific CD8(+) CTL, whereas CD40, B7, and IL-12 costimulation is required for priming of CD4(+) Th cells by ISS-based vaccines...

..Finally, down-regulation of CD94/NKG2 was found to occur only during chronic LCMV infection. Altogether, this study suggests that CD94/NKG2 expression is not necessarily correlated with inhibition of T cell function...

..Thus, CRACC is a unique CD2-like receptor which mediates NK cell activation through a SAP-independent extracellular signal-regulated kinase-mediated pathway...

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..Dependence on perforin function was demonstrated for the cytotoxicity of these effectors in vitro and for the ability of these effectors to reject a variety of tumors in vivo...

..Thus, the sites of TCR and NK receptor interaction with H-2Dd are distinct, an observation consistent with independent modes of TCR and NK receptor evolution and function...

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..Collectively, these findings show that CD2 plays a role in pre-TCR function in double-negative thymocytes, TCR selection events during thymocyte development, and TCR-stimulated cytokine production in mature T cells...

..The mice fail to clear lymphocytic choriomeningitis virus and they eliminate fibrosarcoma tumour cells with reduced efficiency. Perforin is therefore a key effector molecule for T-cell- and natural killer-cell-mediated cytolysis...

..Therefore, in addition to its well-established role in proliferation and differentiation, B-myb also appears to be involved in activation of NK and T cells and in their regulation of Fas/Fas ligand-mediated cytotoxicity..

..We have found that the epidermis is intrinsically resistant to immunologic cytotoxicity, due in large part to resistance of basal keratinocytes and melanocytes to apoptosis induced by ..

The objective of this project is to study immunologic cytotoxicity as a mechanism of discrete cellular lysis in cutaneous disease, with particular emphasis on antibody mediated mechanisms of lysis, especially antibody dependent cellular ..

..factor- related apoptosis-inducing ligand (Apo2L/TRAIL), a key effector of NK cell- and T cell-mediated immunologic cytotoxicity, to induce p53-independent apoptosis of colon cancer cells...

..factor- related apoptosis-inducing ligand (Apo2L/TRAIL), a key effector of NK cell- and T cell-mediated immunologic cytotoxicity, to induce p53-independent apoptosis of colon cancer cells...

..factor- related apoptosis-inducing ligand (Apo2L/TRAIL), a key effector of NK cell- and T cell-mediated immunologic cytotoxicity, to induce p53-independent apoptosis of colon cancer cells...

..major objective of this grant over the past 20 years has been to study key aspects of the mechanisms of immunologic cytotoxicity in skin disease...

..on the surface of epidermal keratinocytes is a prerequisite for leukocyte/keratinocyte attachment and immunologic cytotoxicity of keratinocytes...

..Thus, the candidate will acquire the skills to secure a faculty position as a pediatric bone marrow transplantation clinical-scientist...

..Vaccination with DCs could become an option for patients with earlier disease stages. ..

..Such information may be useful in guiding clinical management, and lay the foundation for possible future vaccines. ..

..Information from the proposed study may allow identification of patients at risk of progression from BKV reactivation to clinical BKV disease and guide therapeutic interventions. ..

..Human IEL are a little-understood compartment of lymphocytes whose interactions with EC have never been studied. Yet, these interactions may be critical to the mucosal immune network...

..Current therapies have the potential to improve outcome in a fraction of patients but are associated with considerable toxicity. Vaccination with melanoma antigen-loaded dendritic cells (DCs) could improve outcomes without toxicity. ..

..The experiments proposed here would lay ground for further use of SCID-hu/DCs mice to study other vaccines and demonstrate development of protective immunity upon in vivo rechallenge. ..

..In this proposal, we present experiments that will shed more light on the molecular mechanism of nef-mediated MHC class I downmodulation. ..

..This grant proposal aims to more fully understand the viral mechanisms for immune escape and viral persistence in order to eradicate infected cells, cure disease and prevent new infection. ..

..This proposal is relevant to the mission of NIH in that it seeks to understand basic mechanisms of how HIV establishes a chronic infection. This work has the potential to have a significant impact on public health. ..

..Studies are proposed to better understand the detailed molecular mechanism of MHC-I downmodulation. These studies should aid in the development of inhibitors that disrupt HIV immune evasion. ..

..This proposal focuses clearly on a pivotal immune control mechanism that will influence many current and future immunotherapies. ..

..The expression by the IL- 10+ CD8+ Ts of various markers associated with regulatory T cells, such as CD25, FoxpS, CTLA-4 will also be assessed. ..

..This proposal is relevant to the mission of NIH in that it seeks to understand basic mechanisms of how HIV establishes a chronic infection. This work has the potential to have a significant impact on public health. ..

..Overall, this proposal will permit us to demonstrate that efficient breast cancer immunity can be generated and used to reject the tumor thus permitting development of novel treatment modalities in breast cancer. ..

..These studies will determine the mechanism of IEL chemotaxis toward secreted products of ECs, why IL-15 is more potent than IL-2 in inducing LAK activity by IELs, and how IL-10 and IL-12 augment this activity. ..

..A complete understanding of the variables that affect CTL recognition of infected cells should help facilitate the development a vaccine and new approaches to the treatment of AIDS. ..

..Memory T cells are essential to provide protection against many infections so this research has substantial impact on understanding immunity and vaccine design. ..

..The experiments proposed will significantly further our knowledge in this area...

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..These studies will provide a comprehensive analysis of the role of lL-15 in regulation of CD8 T cells. ..

..Chaperones and export carriers, tapasin and BAP31 will also be tagged with FP as will viral proteins, the US3 protein of HCMV, and the MCMV proteins m4(p34) and m152. ..

..The immunology and endocrinology of the postpartum provides a lens through which to study autoimmune disease, as the postpartum is a critical period for development or exacerbation of many autoimmune diseases. ..

..Over the long term, this research will help characterize hazards associated with trichothecene exposure that can be used in human risk assessment. ..

..We propose to investigate in this proposal a novel method for overcoming the major obstacle to extending the promising results for inhibiting HSV-2 transmission to HIV, namely getting small RNAs into the immune cells that HIV infects. ..