Alpha phenyl-tert-butyl nitrone (PBN) protects syngeneic marrow transplant recipients from the lethal cytokine syndrome occurring after agonistic CD40 antibody administration.
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.
Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Maria
M
Gendelman
Nadine
N
Halligan
Richard
R
Komorowski
Brent
B
Logan
William J
WJ
Murphy
Bruce R
BR
Blazar
Kirkwood A
KA
Pritchard
William R
WR
Drobyski
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D019013:CD40 Antigens / Q000276:immunology*; D003497:Cyclic N-Oxides; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D008223:Lymphoma / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009589:Nitrogen Oxides / Q000494:pharmacology*; D015996:Survival Rate; D013577:Syndrome; D014180:Transplantation
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D003497:Cyclic N-Oxides; D016207:Cytokines; D009589:Nitrogen Oxides; C029217:phenyl-N-tert-butylnitrone