BACKGROUND: The usefulness of radioimmunotherapy (RIT) for infectious diseases was recently demonstrated for several fungal and bacterial infections, but the mechanisms by which RIT is effective against microbes are uncertain. METHODS: We investigated the interaction between polysaccharide capsule-binding 18B7 monoclonal antibodies (MAbs) labeled with alpha-emitter 213Bi and Cryptococcus neoformans cells as well as between 213Bi-18B7 and components of immune system, both in vitro and in vivo. RESULTS: For 213Bi-18B7, the microbicidal effect was predominantly due to "direct-hit" killing, with some contribution from the "crossfire" effect. The efficacy of cell killing correlated with the binding capacity of the MAb to the capsule and was dependent on the MAb isotype. RIT also promoted the apoptosis-like death of fungal cells. Cooperation was observed in vitro between the antifungal activity of macrophages and RIT, suggesting the potential for synergistic action in vivo. RIT was associated with changes in concentration of the cytokines interleukin (IL)-2, IL-4, IL-10, tumor necrosis factor-alpha, and interferon-gamma, suggesting that the therapeutic effects of RIT may result from changes in the inflammatory response. CONCLUSIONS: The present results suggest that the antimicrobial efficacy of RIT involves killing through promotion of fungal cell apoptosis-like death, reduction in yeast capsule size, cooperation with macrophages, and modulation of the inflammatory response.
BACKGROUND: The usefulness of radioimmunotherapy (RIT) for infectious diseases was recently demonstrated for several fungal and bacterial infections, but the mechanisms by which RIT is effective against microbes are uncertain. METHODS: We investigated the interaction between polysaccharide capsule-binding 18B7 monoclonal antibodies (MAbs) labeled with alpha-emitter 213Bi and Cryptococcus neoformans cells as well as between 213Bi-18B7 and components of immune system, both in vitro and in vivo. RESULTS: For 213Bi-18B7, the microbicidal effect was predominantly due to "direct-hit" killing, with some contribution from the "crossfire" effect. The efficacy of cell killing correlated with the binding capacity of the MAb to the capsule and was dependent on the MAb isotype. RIT also promoted the apoptosis-like death of fungal cells. Cooperation was observed in vitro between the antifungal activity of macrophages and RIT, suggesting the potential for synergistic action in vivo. RIT was associated with changes in concentration of the cytokines interleukin (IL)-2, IL-4, IL-10, tumor necrosis factor-alpha, and interferon-gamma, suggesting that the therapeutic effects of RIT may result from changes in the inflammatory response. CONCLUSIONS: The present results suggest that the antimicrobial efficacy of RIT involves killing through promotion of fungal cell apoptosis-like death, reduction in yeast capsule size, cooperation with macrophages, and modulation of the inflammatory response.
Authors: Luis Ostrosky-Zeichner; Arturo Casadevall; John N Galgiani; Frank C Odds; John H Rex Journal: Nat Rev Drug Discov Date: 2010-08-20 Impact factor: 84.694