Evaluation of the safety of recombinant P-selectin glycoprotein ligand-immunoglobulin G fusion protein in experimental models of localized and systemic infection.
P-selectin is a major component in the early interaction between platelets, endothelial cells, and inflammatory cells in the initial phases of the innate immune response. The major ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1) and this ligand is expressed on the surface of monocyte, lymphocyte, and neutrophil membranes. A truncated form of recombinant human P-selectin glycoprotein ligand-1 has been covalently linked to immunoglobulin G (rPSGL-Ig) and this fusion peptide functions as a competitive inhibitor of PSGL-1. As an inhibitor of neutrophil-endothelial cell adherence, rPSGL-Ig is in early clinical development for the treatment of ischemia reperfusion injury. To determine the potential for deleterious effects from inhibition in P-selectin-mediated neutrophil attachment in the presence of bacterial infection, the effects of therapeutic doses of rPSGL-Ig were tested in three standard laboratory sepsis models. The experimental models included: the murine systemic Listeria monocytogenes infection model, the Pseudomonas aeruginosa bacteremia model in neutropenic rats, and the cecal ligation and puncture (CLP)-induced peritonitis model in rats. Recombinant human PSGL-Ig had no adverse effects on mortality or immune clearance in systemic bacterial infection in any of the three infection models. The PSGL-1 inhibitor did significantly decrease local neutrophil infiltration and bacterial clearance in the peritoneum following CLP, but this did not increase the systemic levels of proinflammatory cytokines, the quantitative levels of bacteremia, or the overall mortality rate following CLP. The results indicate that rPSGL-Ig did not exacerbate infection in these experimental sepsis models.
Opal
S M
SM
Infectious Disease Division, Brown University School of Medicine, Providence, Rhode Island, USA.
Sypek
J P
JP
Keith
J C
JC
Schaub
R G
RG
Palardy
J E
JE
Parejo
N A
NA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D016470:Bacteremia / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D001424:Bacterial Infections / Q000188:drug therapy* / Q000276:immunology; D002432:Cecum / Q000293:injuries; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D016207:Cytokines / Q000097:blood; D003864:Depression, Chemical; D004353:Drug Evaluation, Preclinical; D005260:Female; D005803:Genes, Immunoglobulin; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G / Q000235:genetics; D007416:Intestinal Perforation / Q000150:complications; D008088:Listeriosis / Q000188:drug therapy / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D019007:P-Selectin / Q000502:physiology; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology; D011552:Pseudomonas Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D012449:Safety; D013047:Specific Pathogen-Free Organisms
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011993:Recombinant Fusion Proteins