Administration of either anti-CD40 or interleukin-12 following lethal total body irradiation induces acute lethal toxicity affecting the gut.
Interleukin (IL)-12 and antibodies against CD40 have demonstrated antitumor effects in a variety of in vivo model systems. However, both agents can also mediate significant toxicities either when used following lethal TBI or when administered in combination with other agents such as IL-2. In this study, we assessed the effects of anti-CD40 monoclonal antibody (MoAb) and IL-12 in lethally irradiated mice. Acute lethal toxicity was observed following the administration of either 10 microg anti-CD40 MoAb (FGK45) or 0.5 microg of recombinant murine (rm)IL-12 that resulted in 100% mortality of all mice within 4 to 6 days. Histological evaluation revealed destruction of the normal gut architecture in both anti-CD40 MoAb- and rmIL-12-treated mice. Analysis of serum cytokine levels in the lethally irradiated mice receiving anti-CD40 MoAb demonstrated a marked increase of interferon (IFN)-gamma and IL-12 p40, whereas mice receiving rmIL-12 demonstrated a marked increase of IFN-gamma. Lethally irradiated IL-12 p40 knock-out mice were resistant to anti-CD40-induced toxicity, suggesting that the lack of IL-12 p40 with no possibility of making functional IL- 12 p70 is key for this toxic reaction. Similarly, lethally irradiated IFN-gamma knock-out mice were completely resistant to rmIL-12-induced toxicity, suggesting that IFN-gamma is a major player in IL-12-mediated toxicity. These results suggest that both anti-CD40 MoAb and rmIL-12 induce an acute fatal toxicity characterized by similar intestinal pathology and mediated in part by IFN-gamma.
Hixon
Julie A
JA
SAIC-Frederick, NCI-Frederick, Maryland 21702, USA.
Anver
Miriam R
MR
Blazar
Bruce R
BR
Panoskaltsis-Mortari
Angela
A
Wiltrout
Robert H
RH
Murphy
William J
WJ
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity*; D019013:CD40 Antigens / Q000276:immunology*; D003131:Combined Modality Therapy / Q000401:mortality; D005260:Female; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics / Q000494:pharmacology; D018664:Interleukin-12 / Q000097:blood / Q000502:physiology / Q000633:toxicity*; D053762:Interleukin-12 Subunit p40; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D021122:Protein Subunits / Q000097:blood / Q000502:physiology; D015996:Survival Rate; D014916:Whole-Body Irradiation / Q000401:mortality*
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D018664:Interleukin-12; D007371:Interferon-gamma