Interaction of Radiolabeled Antibodies with Fungal Cells and Components of the Immune System In Vitro and during Radioimmunotherapy for Experimental Fungal Infection
Departments of 1Nuclear Medicine, 2Microbiology and Immunology, and 3Medicine, Albert Einstein College of Medicine, Bronx, New York; 4European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany
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 α‐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–α, and interferon‐γ, 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.
Received 16 September 2005; accepted 30 November 2005; electronically published 13 April 2006.
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Online publication date: 1-Feb-2007.
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Presented in part: 105th annual meeting of the American Society for Microbiology, Atlanta, June 2005 (abstract F‐030).
Potential conflicts of interest: E.D. and A.C. are consultants for Pain Therapeutics. For all other authors, no potential conflicts are reported.
Financial support: National Institutes of Health (grants AI‐52042 and AI‐60507 to E.D. and grants AI‐033142, AI‐033774, and HL‐059842 to A.C.); Fighting Children’s Cancers Foundation (grant to E.D.); European Commission (grants to C.A. and A.M.).