Josephine L. Meade
St James's University Hospital
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Featured researches published by Josephine L. Meade.
Cancer Research | 2007
Yasser M. El-Sherbiny; Josephine L. Meade; Tim D. Holmes; Dennis McGonagle; Sarah L. Mackie; Ann W. Morgan; Gordon Cook; Sylvia Feyler; Stephen J. Richards; Faith E. Davies; Gareth J. Morgan; Graham P. Cook
Recent evidence suggests a role for natural killer (NK) cells in the control of multiple myeloma. We show that expression of the NK cell receptor DNAM-1 (CD226) is reduced on CD56(dim) NK cells from myeloma patients with active disease compared with patients in remission and healthy controls. This suggested that this receptor might play a role in NK-myeloma interactions. The DNAM-1 ligands Nectin-2 (CD112) and the poliovirus receptor (PVR; CD155) were expressed by most patient myeloma samples analyzed. NK killing of patient-derived myelomas expressing PVR and/or Nectin-2 was DNAM-1 dependent, revealing a functional role for DNAM-1 in myeloma cell killing. In myeloma cell lines, cell surface expression of PVR was associated with low levels of NKG2D ligands, whereas cells expressing high levels of NKG2D ligands did not express PVR protein or mRNA. Furthermore, NK cell-mediated killing of myeloma cell lines was dependent on either DNAM-1 or NKG2D but not both molecules. In contrast, the natural cytotoxicity receptor NKp46 was required for the killing of all myeloma cell lines analyzed. Thus, DNAM-1 is important in the NK cell-mediated killing of myeloma cells expressing the cognate ligands. The importance of NKp46, NKG2D, and DNAM-1 in myeloma killing mirrors the differential expression of NK cell ligands by myeloma cells, reflecting immune selection during myeloma disease progression.
PLOS ONE | 2011
Erica B. Wilson; Jehan J. El-Jawhari; Abbie L. Neilson; Geoffrey Hall; Alan Melcher; Josephine L. Meade; Graham P. Cook
Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-β. Release from TGF-β-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-β dependent manner following chronic contact-dependent interactions with tumour cells in vitro. In vivo, NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-β dependent inhibition upon autologous NK cells ex vivo. TGF-β antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-β treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-β blockade and both anti-TGF-β antibodies and a small molecule inhibitor of TGF-β signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-β blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity.
European Journal of Immunology | 2002
Josephine L. Meade; Claire Fernandez; Martin Turner
We have analyzed the effects of deficiency in the tyrosine kinase Lyn on B cell development using transgenic mice that express a B cell antigen receptor (BCR) of defined specificity (3‐83,anti‐H‐2Kk or b). In the absence of Lyn, immature B cells are abundant in the bone marrow and spleen up until the T1 stage (IgMhi IgD– CD21–CD23–), after which B cell development is severely impaired. The small number of mature B cells that do develop in Lyn‐deficient mice express normal levels of the transgenic BCR and lack expression of CD80 and CD86, suggesting they are not activated. In Lyn‐deficient animals the presence of a Bcl‐2 transgene leads to a dramatic increase in B cell numbers and restores T2 stage (IgMhi IgDhi CD21hi CD23int) and mature populations. In 3‐83 lyn–/– Bcl‐2 Tg mice, a population of λ‐positive cells that also express the 383 idiotype is evident, suggesting that in the absence of lyn isotype exclusion by the transgenic BCR is less efficient. The results indicate that Lyn plays a positive role in the selection and survival of mature B cells in addition to its previously documented negative role in tolerance and B cell activation.
European Journal of Immunology | 2004
Josephine L. Meade; Victor L. J. Tybulewicz; Martin Turner
In this study we set out to test whether Syk was required for negative selection of immature B cells. B cells expressing a B cell antigen receptor (BCR) transgene (3–83, anti‐H‐2Kk) underwent negative selection independently of Syk in both fetal liver organ culture and radiation chimera models. Furthermore, Syk‐independent negative selection was not reversed by transgenic overexpression of Bcl‐2. Receptor editing was not apparent in Syk‐deficient B cells, presumably as a consequence of the failure of mature edited B cells to develop in the absence of Syk. Interestingly, light chain isotype exclusion by the BCR transgene failed in the absence of Syk. We observed a dramatic reduction in the overall BCR‐mediated tyrosine phosphorylation of cellular proteins in Syk‐deficient immature B cells. However, the tyrosine phosphorylation of a number of substrates including phospholipase Cγ2, although reduced, was not completely abrogated. BCR ligation triggered an increase in calcium flux in the absence of Syk. Thus signaling events that mediate negative selection can still occur in the absence of Syk. This may be due to redundancy with zeta‐associated protein 70 (ZAP‐70), which we demonstrate to be expressed in immature B cells.
Journal of Immunology | 2009
Josephine L. Meade; Erica B. Wilson; Tim D. Holmes; Erika A. de Wynter; Peter Brett; Liz Straszynski; Paul A. S. Ballard; Joseph A. Trapani; Michael F. McDermott; Graham P. Cook
NK cells induce apoptosis in target cells via the perforin-mediated delivery of granzyme molecules. Cytotoxic human NK cells can be generated by IL-15-mediated differentiation of CD34+ cells in vitro and these cultures have been used extensively to analyze the development of the NK cell surface phenotype. We have used NK cell differentiation in vitro together with protease-deficient human NK cells to analyze the acquisition of the cytotoxic phenotype. Granzymes are synthesized as inactive zymogens and are proteolytically activated by the cysteine protease cathepsin C. Cathepsin C is also synthesized as a zymogen and activated by proteolysis. We show that human NK cells generated in vitro undergo granule exocytosis and induce the caspase cascade in target cells. IL-15 and stem cell factor (IL-15 plus SCF) induced the expression of the granzyme B and perforin genes and the activation of cathepsin C and granzyme B zymogens. Perforin activation is also mediated by a cysteine protease and IL-15 plus SCF-mediated differentiation was accompanied by perforin processing. However, cathepsin C-deficient human NK cells revealed that perforin processing could occur in the absence of cathepsin C activity. The combination of IL-15 plus SCF is therefore sufficient to coordinate the development of the NK cell surface phenotype with the expression and proteolytic activation of the cytotoxic machinery, reflecting the central role of IL-15 in NK cell development.
Biochemical Journal | 2010
Gina B. Scott; Paul Bowles; Erica B. Wilson; Josephine L. Meade; Boon Chuan Low; Adam Davison; G E Blair; Graham P. Cook
Cytotoxic lymphocytes eliminate infected cells and tumours via the perforin-mediated delivery of pro-apoptotic serine proteases known as granzymes. Granzyme B triggers apoptosis via the cleavage of a repertoire of cellular proteins, leading to caspase activation and mitochondrial depolarization. A simple bioinformatics strategy identified a candidate granzyme B cleavage site in the widely expressed BNIP-2 (BCL2/adenovirus E1B-19K protein-interacting protein 2). Granzyme B cleaved recombinant BNIP-2 in vitro and endogenous BNIP-2 was cleaved during the NK (natural killer) cell-mediated killing of tumour cells. Cleavage required the site identified in the bioinformatics screen and was caspase-independent. Expression of either full-length BNIP-2 or a truncated molecule mimicking the granzyme B cleaved form was pro-apoptotic and led to the caspase-dependent cleavage of BNIP-2 at a site distinct from granzyme B cleavage. Inhibition of BNIP-2 expression did not affect the susceptibility to NK cell-mediated killing. Furthermore, target cells in which BID (BH3-interacting domain death agonist) expression was inhibited also remained highly susceptible to NK cell-mediated killing, revealing redundancy in the pro-apoptotic response to human cytotoxic lymphocytes. Such redundancy reduces the opportunity for escape from apoptosis induction and maximizes the chances of immune-mediated clearance of infected cells or tumour cells.
Molecular Immunology | 2014
Jehan J. El-Jawhari; Yasser M. El-Sherbiny; Gina B. Scott; Ruth Morgan; Robin Prestwich; Paul Bowles; G. Eric Blair; Tomoyuki Tanaka; Terence H. Rabbitts; Josephine L. Meade; Graham P. Cook
Mutations in the RAS family of oncogenes are highly prevalent in human cancer and, amongst its manifold effects, oncogenic RAS impairs the expression of components of the antigen presentation pathway. This allows evasion of cytotoxic T lymphocytes (CTL). CTL and natural killer (NK) cells are reciprocally regulated by MHC class I molecules and any gain in CTL recognition obtained by therapeutic inactivation of oncogenic RAS may be offset by reduced NK cell activation. We have investigated the consequences of targeted inactivation of oncogenic RAS on the recognition by both CTL and NK cells. Inactivation of oncogenic RAS, either by genetic deletion or inactivation with an inducible intracellular domain antibody (iDAb), increased MHC class I expression in human colorectal cell lines. The common RAS mutations, at codons 12, 13 and 61, all inhibited antigen presentation. Although MHC class I modulates the activity of both CTL and NK cells, the enhanced MHC class I expression resulting from inactivation of mutant KRAS did not significantly affect the in vitro recognition of these cell lines by either class of cytotoxic lymphocyte. These results show that oncogenic RAS and its downstream signalling pathways modulate the antigen presentation pathway and that this inhibition is reversible. However, the magnitude of these effects was not sufficient to alter the in vitro recognition of tumour cell lines by either CTL or NK cells.
Briefings in Functional Genomics and Proteomics | 2008
Gina B. Scott; Josephine L. Meade; Graham P. Cook
Natural killer (NK) cells are lymphocytes with an innate ability to recognize and kill infected cells and tumour cells. Unlike B and T cells, NK cells do not express an antigen receptor. Instead, NK cells detect changes in the phenotype of the target cell surface; malignant transformation or infection resulting in the loss or gain of particular molecules that are detected by inhibitory or activating receptors on the NK cell surface. The identification and characterization of NK cells and their receptors was made possible by monoclonal antibody technology. The ease with which genes and gene products can now be identified and manipulated has accelerated our understanding of NK cell function. Furthermore, gene and protein profiling studies are beginning to refine our understanding of NK cells, their interactions with other cells and their effector mechanisms. This review illustrates some of the basic features of NK cell biology and highlights the contribution made by post-genomic technology in defining the molecular mechanisms by which NK cells identify and kill susceptible targets.
Blood | 2006
Josephine L. Meade; Erika A. de Wynter; Peter Brett; Saghira Malik Sharif; C. Geoffrey Woods; Alexander F. Markham; Graham P. Cook
Blood | 2003
Patricia Louise Coletta; Albrecht M. Müller; Elena Jones; Bettina Mühl; Sarah Holwell; Deborah Clarke; Josephine L. Meade; Graham P. Cook; Gillian Hawcroft; Frederique Ponchel; Wai K. Lam; Ken MacLennan; Mark A. Hull; Constanze Bonifer; Alexander F. Markham