Inhibition of TNF-alpha produced by Kupffer cells protects against the nonspecific liver toxicity of immunotoxin anti-Tac(Fv)-PE38, LMB-2.

Abstract

LMB-2 (anti-Tac(Fv)-PE38) is a recombinant immunotoxin composed of the Fv fragment of the anti-Tac Ab fused to a 38-kDa form of Pseudomonas: exotoxin A. Recent clinical trials showed that LMB-2 is a promising agent for the treatment of patients with Tac-positive leukemia or lymphoma. One major side effect that needs to be overcome is nonspecific liver toxicity. In the current study, we have analyzed the mechanism of this toxicity using a mouse model. Mice that were injected with a lethal dose of LMB-2 showed severe hepatic necrosis. Immunohistochemistry revealed that LMB-2 accumulated in Kupffer cells in the liver, suggesting that the damage to the hepatocytes was indirect. When we examined the effects of LMB-2 on peritoneal macrophages, cells in the same lineage as Kupffer cells, we found that LMB-2 induced the production of TNF-alpha by these cells. Following LMB-2 administration to mice, the levels of TNF-alpha in the liver increased to very high levels, whereas the rise in serum levels was modest. In addition, the LMB-2-induced liver toxicity was blocked by a specific TNF binding protein (TNFsRp55). Liver toxicity was also blocked by indomethacin, which also blocked the rise of TNF-alpha in the liver. Both TNFsRp55 and indomethacin treatment protected mice against a lethal dose of LMB-2. These data indicate that TNF-alpha produced in the liver by Kupffer cells has an important causal role in the nonspecific liver toxicity of LMB-2. These findings have important clinical implications for the use of immunotoxins in the therapy of patients with cancer.

• Authors: M Onda, M Willingham, Q C Wang, R J Kreitman, Y Tsutsumi, S Nagata, I Pastan
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 165 Issue 12 Pg. 7150-6 (Dec 15 2000) ISSN: 0022-1767 [Print] United States
• PMID: 11120846 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• B3(Fv)-PE38KDEL recombinant immunotoxin
• Cytokines
• Exotoxins
• Immunoglobulin Fragments
• Immunotoxins
• Receptors, Tumor Necrosis Factor
• Receptors, Tumor Necrosis Factor, Type I
• Recombinant Proteins
• Tumor Necrosis Factor-alpha
• immunoglobulin Fv
• Indomethacin

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, metabolism, toxicity)
• Antigens, CD (pharmacology)
• Cytokines (biosynthesis, blood)
• Exotoxins (administration & dosage, metabolism, toxicity)
• Female
• Immunoglobulin Fragments (administration & dosage, metabolism, toxicity)
• Immunotoxins (administration & dosage, metabolism, toxicity)
• Indomethacin (pharmacology)
• Injections, Intravenous
• Kupffer Cells (immunology, metabolism, pathology)
• Liver (immunology, metabolism, pathology)
• Macrophages, Peritoneal (immunology, metabolism)
• Mice
• Pseudomonas (immunology)
• Receptors, Tumor Necrosis Factor
• Receptors, Tumor Necrosis Factor, Type I
• Recombinant Proteins (administration & dosage, immunology, metabolism, toxicity)
• Tumor Cells, Cultured (immunology, metabolism, pathology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, biosynthesis, physiology)