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. Cryptococcus neoformans is an opportunistic yeast that is surrounded by a polysaccharide capsule. The capsule, composed primarily of glucuronoxylomannan (GXM), is a major virulence factor. Biological activities associated with the cryptococcal capsule, the capsular polysaccharide, or purified GXM include induction of immune unresponsiveness (27, 34, 42), inhibition of phagocytosis (8), enhancement of human immunodeficiency virus infectivity in vitro (44), regulation of cytokine secretion (60, 61), suppression of T-cell responses (3-5), and promotion of L-selectin shedding from neutrophils (19). The central role of cryptococcal polysaccharide and GXM in the pathogenesis of cryptococcosis has generated interest in passive immunization with anti-GXM antibodies as an alternative or adjunct to conventional antifungal therapy (20, 40, 50). Opsonization of C. neoformans cells with anticapsular immunoglobulin G (IgG) antibodies reverses the antiphagocytic properties of the cryptococcal capsule (32, 41, 51). Once opsonized, the yeast cells are readily engulfed and killed by macrophages and neutrophils (16, 32, 36, 37). In the course of studies on the efficacy of passive immunization in mice, we encountered an acute, toxic reaction that appeared within 10 min after injection of anti-GXM monoclonal a...
