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Produced by Kupffer Cells Protects Against the Nonspecific Liver Toxicity of Immunotoxin Anti-Tac(Fv)-PE38, LMB-2
*
Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27106
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-
by these cells.
Following LMB-2 administration to mice, the levels of TNF- 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- in the
liver. Both TNFsRp55 and indomethacin treatment protected mice against
a lethal dose of LMB-2. These data indicate that TNF- 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.
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