Inhibition of TNF-alpha produced by Kupffer cells protects against the nonspecific liver toxicity of immunotoxin anti-Tac(Fv)-PE38, LMB-2.
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.
Onda
M
M
Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Willingham
M
M
Wang
Q C
QC
Kreitman
R J
RJ
Tsutsumi
Y
Y
Nagata
S
S
Pastan
I
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D015703:Antigens, CD / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D005098:Exotoxins / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D005260:Female; D007128:Immunoglobulin Fragments / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D000922:Immunotoxins / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D007213:Indomethacin / Q000494:pharmacology; D007275:Injections, Intravenous; D007728:Kupffer Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011549:Pseudomonas / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D016207:Cytokines; D005098:Exotoxins; D007128:Immunoglobulin Fragments; D000922:Immunotoxins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C055966:immunoglobulin Fv; D007213:Indomethacin