The molecular mechanisms underlying lymphocyte extravasation remain poorly characterized. We have recently identified junctional adhesion molecule-2 (JAM-2), and have shown that antibodies to JAM-2 stain high endothelial venules (HEVs) within lymph nodes and Peyer patches of adult mice. Here we show that mouse lymphocytes migrate in greater numbers across monolayers of endothelioma cells transfected with JAM-2. The significance of these findings to an understanding of both normal and pathologic lymphocyte extravasation prompted us to clone the human homologue of JAM-2. We herein demonstrate that an anti-JAM-2 antibody, or a soluble JAM-2 molecule, blocks the transmigration of primary human peripheral blood leukocytes across human umbilical vein endothelial cells expressing endogenous JAM-2. Furthermore, we show that JAM-2 is expressed on HEVs in human tonsil and on a subset of human leukocytes, suggesting that JAM-2 plays a central role in the regulation of transendothelial migration.
Cultured myoblasts derived from limb muscle of newborn rats express thrombin receptor immunoreactivity on their surface. Receptor expression is repressed upon myoblast fusion. This is due at least in part to a decrease in the amount of the thrombin receptor mRNA. Addition of thrombin triggers calcium transients only in monobut not multinucleated muscle cells. Furthermore, thrombin increases the rate of myoblast proliferation that coincides with an activation of mitogen-activated protein kinase. Northern analysis of thrombin receptor mRNA expression in skeletal muscle showed that the transcript is present at a relatively high level at birth, but is almost undetectable in the adult. By in situ hybridization, the mRNA at birth appeared to be present mostly in mononucleated cells grouped in clusters, but not in muscle fibers. Very few nuclei surrounded by a mRNA signal were present on muscle sections of rats 24 days postnatally. These results suggest that the thrombin receptor plays a role in muscle development.Most of the cellular effects of thrombin are mediated via the thrombin receptor (ThR).1 This receptor is a member of the G protein-coupled receptor family and is activated by cleavage of an Arg-Ser bond within its N-terminal extracellular domain (1, 2). The new N terminus generated by this proteolytic event acts as a tethered ligand for the receptor (1, 3). Synthetic peptides corresponding to the newly created N terminus mimic the effects of thrombin in mobilizing Ca 2ϩ in Xenopus oocytes microinjected with ThR mRNA, in causing platelet aggregation (1) and in several other systems (4) including neuronal cells (5, 6). Recently ThR knockout mice were generated (7). Half the mutant embryos die at embryonic day 9 -10, whereas the rest continue to develop without any obvious phenotype. However, platelets of the surviving animals degranulate and aggregate in response to thrombin. It was therefore suggested that the ThR plays a role in development and that there is a second receptor which can be activated by thrombin (7).During the course of muscle development, muscle cell precursors migrate from the somites to the limbs where they continue to proliferate and eventually align and fuse to form multinucleated myotubes that are irreversibly postmitotic. The identity of the factors that control myoblast proliferation and differentiation in vivo is not known. From in vitro work, however, several agents have been shown to play a role in these processes. For example, fibroblast and epidermal growth factors are mitogenic for myoblastic cells and inhibit their differentiation (8, 9), whereas transforming growth factor- suppresses only differentiation (10, 11). As muscle differentiation ultimately involves the generation of postmitotic multinucleated cells, it is essential that pathways leading to DNA synthesis are shut down in muscle fibers.The cellular effects of thrombin have been most intensely studied in blood and blood vessels. Thrombin for example activates platelets (12), chemoattracts neutrophils (13, 14), activates...
(2010) EB66 cell line, a duck embryonic stem cell-derived substrate for the industrial production of therapeutic monoclonal antibodies with enhanced ADCC activity, mAbs, 2:4, 405-415,
Purpose: Various proapoptotic agents are currently being explored to improve the outcome of radiotherapy. We have evaluated whether APO010öa novel recombinant ligand of the Fas/ CD95 death receptoröenhanced the cytotoxic effect of radiation on lymphoid and solid tumor cell types. Experimental Design: A Bcl-2^overexpressingT-leukemic cell line (Jurkat), a colon carcinoma cell line (HCT116), and a mesothelioma cell line were used as model systems in vitro and in a subcutaneous transplant setting in immunodeficient mice. Sensitivity to single and combined treatment was read out by apoptosis hallmarks and clonogenic survival in vitro, and by tumor growth delay using bioluminescence and palpation in vivo. Results: Whereas the three cell lines resisted apoptosis induction by irradiation and APO010 alone, combined treatment greatly enhanced their apoptotic response. In clonogenic survival assays, APO010 reduced the outgrowth of Jurkat-Bcl-2 and HCT116 cells and sensitized the mesothelioma cell line to radiation. In vivo, systemic treatment with APO010 alone caused tumor growth delay in Jurkat-Bcl-2 and HCT116 cells. However, APO010 did not improve the efficacy of radiotherapy in any of the model systems at the selected single dose, which had moderate and reversible systemic toxicity. Conclusions: Although APO010 and radiation had a clear combined cytotoxic effect on tumor cells in vitro, a combined therapeutic effect was not achieved on the same cells subcutaneously grafted in mice, at APO010 doses approximating the maximally tolerable level. These findings suggest that it will be difficult to identify a therapeutic window for this combined modality approach in a clinical setting.
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