title: Anti-CD44 monoclonal antibody (IM7) induces murine systemic shock mediated by platelet activating factor.
abstract: The cell adhesion molecule CD44 plays an important role in progression of autoimmune diseases or cancer. Administration of anti-CD44 monoclonal antibodies (mAbs) have been reported to have anti-inflammatory or anti-cancer activity. However, our evidence shows that intravenous administration of the anti-CD44 IgG2b mAb IM7 induces systemic shock in mice. To examine the character of systemic shock, the cutaneous excess vascular permeability was evaluated. Administered mAb markedly increased vascular permeability but its F(ab')(2) fragments did not induce a reaction. The platelet-activating factor (PAF) specific antagonist Y-24180 was effective in preventing IM7-induced extravasation, whereas anti-histaminergic and anti-serotonergic agents were not. Y-24180 also ameliorated hematocrit elevation and hypotension in mice treated with IM7. These results indicate that IM7-induced systemic shock is mediated by PAF. Because IM7 also binds human CD44, anti-CD44 immunotherapy using IM7 may be applied to the clinical treatment of autoimmune diseases or cancer. This study describes potential triggering pathways for shock that must be avoided through modification of the immunotherapy.
authors.affiliation: National Institute of Advanced Industrial Science and Technology (AIST), University of Tsukuba, Ibaraki, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Makiyama
authors.forename: Youji
authors.initials: Y
authors.lastname: Mitsui
mesh_terms: D000707:Anaphylaxis / Q000276:immunology*; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D001381:Azepines / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D003533:Cyproheptadine / Q000008:administration & dosage / Q000494:pharmacology; D004155:Diphenhydramine / Q000008:administration & dosage / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000276:immunology*; D007022:Hypotension / Q000378:metabolism; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology
chemical_list: D018926:Anti-Allergic Agents; D000911:Antibodies, Monoclonal; D001381:Azepines; D018960:Hyaluronan Receptors; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D010972:Platelet Activating Factor; D014230:Triazoles; C068035:4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6,9-dimethyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepine; D003533:Cyproheptadine; D004155:Diphenhydramine