ACUTE LETHAL TOXICITY FOLLOWING PASSIVE-IMMUNIZATION FOR TREATMENT OFMURINE CRYPTOCOCCOSIS

Passive immunization with monoclonal antibodies (MAbs) specific for th e major capsular polysaccharide of Cryptococcus neoformans alters the course of murine cryptococcosis. During studies of passive immunizatio n for treatment of murine cryptococcosis, we noted the occurrence of a n acute, lethal toxicity. Toxicity was characterized by scratching, le thargy, respiratory distress, collapse, and death within 20 to 60 min after injection of antibody, The toxic effect was observed only in mic e with a cryptococcal infection and was reduced or absent in the early and late stages of disease. The clinical course and histopathology we re consistent with those for shock, There was considerable variation b etween 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 t he Simonsen colony were resistant, Acute toxicity was mimicked by inje ction of preformed complexes of MAb and purified polysaccharide. The t oxic effect was also produced by injection of MAbs into mice that were preloaded with polysaccharide, The toxic effect was not blocked by tr eatment of mice with chloropheniramine or anti-tumor necrosis factor a lpha antibodies or by depletion of complement components via pretreatm ent with cobra venom factor. Toxicity was reduced by treatment of mice with high doses of epinephrine, dexamethasone, or chlorpromazine. Fin ally, the toxic effect was completely blocked by treatment of mice wit h the platelet-activating factor antagonist WEB 2170 BS or by pretreat ment of mice with the liposome-encapsulated drug dichloromethylene dip hosphonate, a procedure which depletes macrophages from the spleen and liver.