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.
Gendelman
Maria
M
Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Halligan
Nadine
N
Komorowski
Richard
R
Logan
Brent
B
Murphy
William J
WJ
Blazar
Bruce R
BR
Pritchard
Kirkwood A
KA
Drobyski
William R
WR
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