Inhibition of TNF-α 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-α by these cells. Following LMB-2 administration to mice, the levels of TNF-α 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-α in the liver. Both TNFsRp55 and indomethacin treatment protected mice against a lethal dose of LMB-2. These data indicate that TNF-α 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.

Hepatic DR5 Induces Apoptosis and Limits Adenovirus Gene Therapy Product Expression in the Liver

“…We and other investigators have shown that AdCMVLacZ treatment leads to induction of TNF-␣, which has been proposed to be produced by Kupffer cells in the liver (27). Consistent with our previous report (54) therapy.…”

Acute Toxicity of Pierisin-1, a Cytotoxic Protein From Pieris Rapae, in Mouse and Rat

“…Immunosuppression of mice by pretreatment with irradiation (500 rad) or by injection of cyclophosphamide or by concurrent use of cortisone acetate reduced or eliminated markedly the development of VLS (Onda et al, 2000). Similarly, VLS was not observed in nude mice receiving IL-2 (Onda et al, 2000). Based on these findings, immune response was considered to have an important role in the pathogenesis of VLS.…”

“…Interleukin-2 (IL-2) induces VLS in mice and tumor necrosis factor-α (TNF-α) plays a central role in their mechanism (Rosenstain et al, 1986;Dubinett et al, 1994). Immunosuppression of mice by pretreatment with irradiation (500 rad) or by injection of cyclophosphamide or by concurrent use of cortisone acetate reduced or eliminated markedly the development of VLS (Onda et al, 2000). Similarly, VLS was not observed in nude mice receiving IL-2 (Onda et al, 2000).…”

Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice

“…Perhaps, this was not surprising since previous clinical reports documented hepatotoxicity with IT administration. [51][52][53][54] Our studies showed a direct relationship in the elevation of liver function enzymes with an increase in the concentration and total dose of DTIL13. We suspected hepatotoxicity of DTIL13, because investigators previously showed that IL13R and IL-4R were expressed FIGURE 9 -Liver enzymes in mice given DTIL13.…”