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Blood, 1 January 2005, Vol. 105, No. 1, pp. 428-431.
Prepublished online as a Blood First Edition Paper on August 26, 2004; DOI 10.1182/blood-2004-01-0371.


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TRANSPLANTATION
Brief report

Alpha phenyl-tert-butyl nitrone (PBN) protects syngeneic marrow transplant recipients from the lethal cytokine syndrome occurring after agonistic CD40 antibody administration

Maria Gendelman, Nadine Halligan, Richard Komorowski, Brent Logan, William J. Murphy, Bruce R. Blazar, Kirkwood A. Pritchard, Jr, and William R. Drobyski

From the Bone Marrow Transplant Program and the Departments of Medicine, Pathology, Biostatistics, and Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI; the Department of Microbiology and Immunology, University of Nevada-Reno, Reno, NV; and the Department of Pediatrics, University of Minnesota, Minneapolis, MN.

Administration of agonistic monoclonal antibodies or recombinant cytokines is a potential approach to enhance antitumor immunity in bone marrow (BM) transplant recipients, but is complicated by toxicity due to proinflammatory cytokine-mediated vital organ damage. We used a murine syngeneic bone marrow transplant (BMT) model, in which administration of anti-CD40 antibody early after BMT results in overproduction of interleukin-12 (IL-12) and interferon-{gamma} (IFN-{gamma}), and lethal gut toxicity to examine the protective effect of the spin trap inhibitor, alpha phenyl-tert-butyl nitrone (PBN). Administration of PBN protected transplant recipients from mortality by significantly attenuating gut toxicity, but did not effect a reduction in the levels of proinflammatory cytokines (IL-12, IFN-{gamma}, tumor necrosis factor {alpha} [TNF-{alpha}], or nitrate/nitrite). Moreover, PBN did not compromise anti-CD40 antibody-mediated antitumor effects in a nontransplantation lymphoma model. Collectively, these data suggest that PBN administration may represent a novel approach for reduction of toxicity without compromise of antitumor effects resulting from administration of therapeutic antibodies in both transplantation and nontransplantation settings. (Blood. 2005;105:428-431)


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