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    ABSTRACT: Cardiovascular disease is the leading cause of death in several countries. The underlying process is atherosclerosis, a slowly progressing chronic disorder that can lead to intravascular thrombosis. There is overwhelming evidence for the underlying importance of our immune system in atherosclerosis. Monocytes, which comprise part of the innate immune system, can be recruited to inflamed endothelium and this recruitment has been shown to be proportional to the extent of atherosclerotic disease. Monocytes undergo migration into the vasculature, they differentiate into macrophage phenotypes, which are highly phagocytic and can scavenge modified lipids, leading to foam cell formation and development of the lipid-rich atheroma core. This increased influx leads to a highly inflammatory environment and along with other immune cells can increase the risk in the development of the unstable atherosclerotic plaque phenotype. The present review provides an overview and description of the immunological aspect of innate and adaptive immune cell subsets in atherosclerosis, by defining their interaction with the vascular environment, modified lipids and other cellular exchanges. There is a particular focus on monocytes and macrophages, but shorter descriptions of dendritic cells, lymphocyte populations, neutrophils, mast cells and platelets are also included.
    Preview · Article · Sep 2013 · Clinical Science
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    ABSTRACT: Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells protect vertebrates by killing infected or transformed cells using granzyme B (GrB) to induce apoptosis. However, GrB-induced apoptosis of target cells causes inflammatory disease and chronic transplant rejection and so is an important disease target. The aim of this study was to prevent apoptosis of the target cells by delivering a plasmid encoding GrB inhibitor proteinase inhibitor-9 (PI-9) using cationic polymers as a non-viral vector. Polyethyleneimine (PEI, branched, Mn 10 kDa) gives a high degree of gene transfection efficiency in many types of cell lines, but it is highly cytotoxic. To reduce this cytotoxicity, we modified PEI by blocking primary amine groups through nucleophilic addition between primary amine and a protected mannose-functionalized cyclic carbonate (MTC-ipman), generating a carbamate linkage through the ring-opening of the cyclic carbonate. Deprotection of the mannose yielded a PEI polymer that is decorated with the carbohydrate. PEI with 7 or 20 of 67 primary amine groups substituted by the carbohydrate had similar gene binding ability compared to unmodified PEI, leading to almost 100% transfection efficiency of a GFP-reporter plasmid in HEK293T human embryonic kidney cells. Furthermore, modification of PEI resulted in a decrease in the cytotoxicity of PEI/DNA complexes. However, PEI with all primary amine groups blocked was unable to form a complex with DNA, and so reporter transfection was negligible. The PI-9 encoding plasmid was transfected into HEK293T cells effectively using the modified PEIs with the optimal degree of primary amine substitution, protecting up to 80% HEK293T cells from killing by human natural killer-like leukemic YT cells. Therefore, these carbamate-mannose modified PEI/PI-9 encoding plasmid complexes have potential clinical utility in the prevention of chronic transplant rejection and inflammatory disease caused by GrB.
    No preview · Article · May 2013 · Biomaterials
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    ABSTRACT: Serine Proteases control a wide variety of physiological and pathological processes in multi-cellular organisms, including blood clotting, cancer, cell death, osmo-regulation, tissue re-modeling and immunity to infection. T lymphocytes are required for adaptive cell mediated immunity and serine proteases are not only important for effector function but also homeostatic regulation of cell numbers. Serine Proteases Inhibitors (Serpins) are the physiological regulators of serine proteases activity. In this review, I will discuss the role of serpins in controlling the recognition of antigen, effector function and homeostatic control of T lymphocytes through the inhibition of physiological serine protease targets. An emerging view of serpins is that they are important promoters of cellular viability through their inhibition of executioner proteases. This will be discussed in the context of the T lymphocyte survival during effector responses and the development and persistence of long-lived memory T cells. The potent anti-apoptotic properties of serpins can also work against adaptive cell immunity by protecting viruses and tumors from eradication by cytotoxic T cells (CTL). Recent insights from knock-out mouse models demonstrate that these serpins also are required for hematological progenitor cells and so are critical for the development of lineages other than T lymphocytes. Given the emerging role of serpins in multiple aspects of lymphocyte immunity and blood development I will review the progress to date in developing new immunotherapeutic approaches based directly on serpins or knowledge gained from identifying their physiologically relevant protease targets.
    No preview · Article · Apr 2013 · Immunology letters
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