title: Acute lethal toxicity following passive immunization for treatment of murine cryptococcosis.
abstract: Passive immunization with monoclonal antibodies (MAbs) specific for the major capsular polysaccharide of Cryptococcus neoformans alters the course of murine cryptococcosis. During studies of passive immunization for treatment of murine cryptococcosis, we noted the occurrence of an acute, lethal toxicity. Toxicity was characterized by scratching, lethargy, respiratory distress, collapse, and death within 20 to 60 min after injection of antibody. The toxic effect was observed only in mice with a cryptococcal infection and was reduced or absent in the early and late stages of disease. The clinical course and histopathology were consistent with those for shock. There was considerable variation between mouse strains in susceptibility to toxicity. Swiss Webster mice from the Charles River colony were most susceptible, followed by C3H/He, BALB/c, and C57BL/6 mice. DBA/2 mice and Swiss Webster mice from the Simonsen colony were resistant. Acute toxicity was mimicked by injection of preformed complexes of MAb and purified polysaccharide. The toxic effect was also produced by injection of MAbs into mice that were preloaded with polysaccharide. The toxic effect was not blocked by treatment of mice with chloropheniramine or anti-tumor necrosis factor alpha antibodies or by depletion of complement components via pretreatment with cobra venom factor. Toxicity was reduced by treatment of mice with high doses of epinephrine, dexamethasone, or chlorpromazine. Finally, the toxic effect was completely blocked by treatment of mice with the platelet-activating factor antagonist WEB 2170 BS or by pretreatment of mice with the liposome-encapsulated drug dichloromethylene diphosphonate, a procedure which depletes macrophages from the spleen and liver.
authors.affiliation: Department of Microbiology, University of Nevada, Reno 89557, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Savoy
authors.forename: D M
authors.initials: DM
authors.lastname: Lupan
authors.forename: P B
authors.initials: PB
authors.lastname: Manalo
authors.forename: J S
authors.initials: JS
authors.lastname: Roberts
authors.forename: A M
authors.initials: AM
authors.lastname: Schlageter
authors.forename: L C
authors.initials: LC
authors.lastname: Weinhold
authors.forename: T R
authors.initials: TR
authors.lastname: Kozel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000633:toxicity*; D000936:Antigen-Antibody Complex / Q000276:immunology / Q000633:toxicity; D001381:Azepines / Q000494:pharmacology; D002744:Chlorpheniramine / Q000494:pharmacology; D002746:Chlorpromazine / Q000494:pharmacology; D004002:Clodronic Acid / Q000494:pharmacology; D003165:Complement System Proteins / Q000378:metabolism; D003453:Cryptococcosis / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology; D004546:Elapid Venoms / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D007116:Immunization, Passive / Q000009:adverse effects*; D007132:Immunoglobulin Isotypes / Q000276:immunology / Q000502:physiology; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011134:Polysaccharides / Q000009:adverse effects / Q000276:immunology* / Q000494:pharmacology; D012769:Shock / Q000276:immunology / Q000382:microbiology; D013047:Specific Pathogen-Free Organisms; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D001381:Azepines; D004546:Elapid Venoms; D007132:Immunoglobulin Isotypes; D011134:Polysaccharides; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid; D002744:Chlorpheniramine; C027478:glucuronoxylomannan; D003907:Dexamethasone; D003165:Complement System Proteins; C063964:bepafant; D002746:Chlorpromazine; D004837:Epinephrine