Detrimental Effects of an Antibody Directed Against Tumor Necrosis Factor Alpha in Experimental Kidney Irradiation

Abstract

Antibodies directed against tumor necrosis factor (TNF)-α are clinically used for Crohn's disease, rheumatoid arthritis and psoriasis. TNF-α is also an important cytokine in radiotherapy because it mediates inflammatory responses in normal tissues. To study the influence of TNF-α inhibition on radiation toxicity, we used a well-established mouse model of kidney irradiation, where the portal also includes parts of the intestine. Mice were treated with single-fraction radiotherapy to the right kidney with doses of 8 or 10 Gy with or without the monoclonal TNF-α antibody infliximab injected i.v. in three doses. The kidney function was assessed by means of repeated ^99mTc-dimercaptosuccinate scans during a maximum follow-up of 49 weeks. Treatment with infliximab significantly exacerbated radiation nephropathy at all time points, both in the 8 Gy and 10 Gy groups. The drug itself is not known to cause renal impairment. In the control group irradiated with 10 Gy, one mouse died from delayed radiation-induced intestinal toxicity. Skin reactions and general performance status were also similar across the groups. These data suggest that administration of infliximab concomitant to radiotherapy causes profound alterations in the development of kidney dysfunction. Importantly, other radiation-related toxicities were similar across all groups.