Monocytes contribute to the development of atherosclerotic lesions in mouse models. The chemoattractant proteins (chemokines), monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), are found in human atheroma, and mice lacking receptors for these chemokines are less susceptible to atherosclerosis and have fewer monocytes in vascular lesions. Although MCP-1 has a powerful effect on monocytes, IL-8 is thought to act predominantly on neutrophils and it is unclear how it could recruit monocytes. Here we investigate the ability of chemokines to control the interaction of monocytes under flow conditions with vascular endothelium that has been transduced to express specific leukocyte-adherence receptors. We find that MCP-1 and IL-8 can each rapidly cause rolling monocytes to adhere firmly onto monolayers expressing E-selectin, whereas related chemokines do not. These effects do not correlate with either the induction of a calcium transient or chemotaxis. We conclude that chemokines are important modulators of monocyte-endothelial interactions under flow conditions. Moreover, our finding that IL-8 is a powerful trigger for firm adhesion of monocytes to vascular endothelium reveals an unexpected role for this chemokine in monocyte recruitment.

Abstract. Leukocyte interactions with vascular endothelium at sites of inflammation can be dynamically regulated by activation-dependent adhesion molecules. Current models, primarily based on studies with polymorphonuclear leukocytes, suggest the involvement of multiple members of the selectin, integrin, and immunoglobulin gene families, sequentially, in the process of initial attachment (rolling), stable adhesion (arrest), spreading and ultimate diapedesis. In the current study, IL-4-activated human umbilical vein endothelium, which selectively expresses VCAM-1 and an L-selectin ligand but not E-selectin, and appropriate function blocking monoclonal antibodies, were used to study monocyte-endothelial interactions in an in vitro model that mimics microcirculatory flow conditions. In this system, L-selectin mediates monocyte rolling and also facilitates ouBl-integdn-dependent arrest, whereas/~-integrins are required for spreading of firmly attached monocytes on the endothelial cell surface but not their arrest. These findings provide the first in vitro evidence for human monocyte rolling on cytokine-activated endothelium, and suggest a sequential requirement for both/~1-and/~2-integfin-dependent adhesive mechanisms in monocyte-endothelial interactions.p ERIPHERAL blood monocytes interact with the vascular endothelial lining as an initial step in a wide range of pathological processes including acute and chronic inflanunation, immune reactions, and atherosclerosis (12,13,45). As a consequence of their transendothelial migration, monocytes are recruited into tissues, organs and body cavities, undergo maturation to macrophages, and participate in defending the host against invading pathogens and regulating the behavior of vascular and non-vascular cells through the secretion of cytokines and other chemical mediators.Early in vitro studies of monocyte adhesion to cultured endothelial cells were typically performed under static conditions and indicated that basal adhesion of purified blood monocytes was relatively high

This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 ؉ 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow-derived plasma cells was reliably saturated (> 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens. (Blood. 2012;120(3):552-559) IntroductionMultiple myeloma (MM) is an incurable malignancy arising from postgerminal mature B cells, characterized by an excess of monotypic plasma cells in the bone marrow and elevated levels of monoclonal immunoglobulins in the serum and/or urine. 1 Common clinical sequelae include lytic bone lesions, fractures, myelosuppression, and renal failure. In the United States, the estimated annual diagnosed incidence is 20 000, with a prevalence of approximately 62 000 as of 2007. 2,3 MM accounts for 15% of all hematologic malignancies and 2% of all malignancies. 4 Advances in high-dose chemotherapy and stem cell transplantation have improved overall survival (OS) and event-free disease periods in MM, 5-7 although relapses are inevitable. Newer therapeutic agents, such as bortezomib, thalidomide, and lenalidomide, have demonstrated clinical benefit in patients with newly diagnosed [8][9][10][11][12][13] and relapsed or refractory disease. 5,14,15 Despite these therapeutic advances, longterm control of relapsed/refractory MM remains elusive for most patients. Progressive disease that is resistant to both immunomodulatory drugs and bortezomib is associated with a particularly poor prognosis. 16 As such, there remains an important need for additional novel therapies to augment existing first-generation agents and continue to improve patient outcome.Elotuzumab is a humanized monoclonal IgG1 antibody directed against human CS1 (also known as CD2 subset-1, SLAMF7, CRACC, and CD319), a cell surface antigen glycoprotein that is highly expressed on MM cells and normal plasma cells. CS1 is expressed at a lower ...

Study design: A literature review of worldwide epidemiology of spinal cord injury (SCI). Objectives: To review the epidemiological indicators of SCI, such as incidence, prevalence, demographic characteristics, etiology, level and severity of injury, complications and mortality.

Leukocyte adhesion to vascular endothelium under flow involves an adhesion cascade consisting of multiple receptor pairs that may function in an overlapping fashion. P-selectin glycoprotein ligand-1 (PSGL-1) and L-selectin have been implicated in neutrophil adhesion to P- and E-selectin under flow conditions. To study, in isolation, the interaction of PSGL-1 with P-and E-selectin under flow, we developed an in vitro model in which various recombinant regions of extracellular PSGL-1 were coupled to 10-μm-diameter microspheres. In a parallel plate chamber with well defined flow conditions, live time video microscopy analyses revealed that microspheres coated with PSGL-1 attached and rolled on 4-h tumor necrosis factor-α–activated endothelial cell monolayers, which express high levels of E-selectin, and CHO monolayers stably expressing E-or P-selectin. Further studies using CHO-E and -P monolayers demonstrate that the first 19 amino acids of PSGL-1 are sufficient for attachment and rolling on both E- and P-selectin and suggest that a sialyl Lewis x–containing glycan at Threonine-16 is critical for this sequence of amino acids to mediate attachment to E- and P-selectin. The data also demonstrate that a sulfated, anionic polypeptide segment within the amino terminus of PSGL-1 is necessary for PSGL-1–mediated attachment to P- but not to E-selectin. In addition, the results suggest that PSGL-1 has more than one binding site for E-selectin: one site located within the first 19 amino acids of PSGL-1 and one or more sites located between amino acids 19 through 148.