Discovery of a potent nanoparticle P‐selectin antagonist with anti‐inflammatory effects in allergic airway disease

The severity of allergic asthma is dependent, in part, on the intensity of peribronchial inflammation. P‐selectin is known to play a role in the development of allergen‐induced peribronchial inflammation and airway hyperreactivity. Selective inhibitors of P‐selectin‐ mediated leukocyte endothelial‐cell interactions may therefore attenuate the inflammatory processes associated with allergic airway disease. Novel P‐selectin inhibitors were created using a polyvalent polymer nanoparticle capable of displaying multiple synthetic, low molecular weight ligands. By assembling a particle that presents an array of groups, which as monomers interact with only low affinity, we created a construct that binds extremely efficiently to P‐ selectin. The ligands acted as mimetics of the key binding elements responsible for the high‐ avidity adhesion of P‐selectin to the physiologic ligand, PSGL‐1. The inhibitors were initially evaluated using an in vitro shear assay system in which interactions between circulating cells and P‐selectin‐coated capillary tubes were measured. The nanoparticles were shown to preferentially bind to selectins expressed on activated endothelial cells. We subsequently demonstrated that nanoparticles displaying P‐selectin blocking arrays were functionally active in vivo, significantly reducing allergen‐induced airway hyperreactivity and peribronchial eosinophilic inflammation in a murine model of asthma.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154265/1/fsb2fj030166fje-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154265/2/fsb2fj030166fje.pd

Mechanisms of drug-induced lupus. III. Sex-specific differences in T cell homing may explain increased disease severity in female mice

Objective . To determine if sex-specific differences in lymphocyte trafficking could contribute to increased disease severity in female mice. Methods . A lupus-like disease was induced by injecting male and female mice with procainamide-treated T cell clones. Trafficking was examined by labeling the injected cells with 51 Cr or 5-chloromethylfluorescein diacetate. Results . Females developed more autoimmune liver disease and greater titers of anti-DNA antibodies than did males, and 2-7 times more cells accumulated in the female spleens. Splenectomy prevented the development of autoantibodies and renal and liver disease. Oophorectomy decreased the splenic homing, autoantibody titer, and liver disease severity, to levels found in males. Conclusion . T cells traffic differently to the spleen in male and female mice, and the spleen appears to be essential in the disease process. This suggests that differences in T cell homing could contribute to sex-specific disease severity in this murine model, and also possibly in human disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37813/1/1780400719_ftp.pd

Thrombospondin production and thrombospondin-mediated adhesion in U937 cells

U937 cells have low levels of surface thrombospondin (TSP) under control conditions but express higher levels after treatment for 1 day with 100 nM phorbol myristate acetate (PMA). Increased surface expression is due, in part, to increased biosynthesis. Untreated U937 cells do not adhere to TSP-coated plastic culture dishes but adhere strongly to TSP after stimulation with PMA. Untreated U937 cells also adhere weakly to endothelial cell monolayers while PMA-treated U937 cells attach strongly to monolayers of rat pulmonary artery endothelial cells. Endothelial cell adhesion appears to be mediated, in part, by TSP since antibodies to TSP partially inhibit.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29248/1/0000305.pd

Intratumoral IL-12 and TNF-α–Loaded Microspheres Lead To Regression of Breast Cancer and Systemic Antitumor Immunity

Background: Local, sustained delivery of cytokines at a tumor can enhance induction of antitumor immunity and may be a feasible neoadjuvant immunotherapy for breast cancer. We evaluated the ability of intratumoral poly-lactic-acid-encapsulated microspheres (PLAM) containing interleukin 12 (IL-12), tumor necrosis factor α (TNF-α), and granulocyte-macrophage colony stimulating factor (GM-CSF) in a murine model of breast cancer to generate a specific antitumor response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41401/1/10434_2004_Article_147.pd

Hematology / Oncology

In the hematology sequence, students learn to recognize and diagnose anemias, bleeding and clotting disorders, and abnormal white blood cell and lymphocyte disorders. Students learn the clinical approach to a patient with a red blood cell, hemostatic or thrombotic, and white blood cell disorder.http://deepblue.lib.umich.edu/bitstream/2027.42/120531/1/medical_m2_curriculum_hematology_oncology-July10.zi

Possible role for cell surface carbohydrate-binding molecules in lymphocyte recirculation..J

ABSTRACT We are investigating the hypothesis that carbohydrate-binding molecules on the cell surface are involved in the recirculation of lymphocytes from the bloodstream into lymphoid organs. This phenomenon requires the specific attachment of circulating lymphocytes to the endothelial cells of postcapillary venules. Using an in vitro assay to measure the adhesive interaction between lymphocytes and postcapillary venules, we have found that L-fucose, D-mannose, and the L-fucose-rich, sulfated polysaccharide fucoidin specifically inhibit this binding interaction. L-fucose shows stereo-selective inhibitory activity at concentrations>18 mM while fucoidin produces 50 % inhibition at ~1-5 x 10-0 M. Fucoidin appears to interact with the lymphocyte, and not the postcapillary venule, to inhibit binding. These data suggest that cell surface carbohydrates (fucoselike) and carbohydrate-binding molecules (cell surface lectins) may contribute to the specific attachment of lymphocytes to postcapillary venules. Normal lymphocytes circulate repeatedly through the bloodstream, tissues and lymphatic system (1, 2). This phenomenon has been termed "recirculation " and is thought to be critical to the normal function of the immune system, perhaps ensurin