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Acute toxicity of an anti-Fas antibody in mice
C Kakinuma1, K Takagaki, T Yatomi
1Toxicology Laboratory, Mochida Pharmaceutical Co., Ltd., Fujieda, Shizuoka, Japan.
Abstract:
By histopathologic examination of various organs in 3 normal strains, C3H/HeN, ICR, and DBA/1J, of mice treated intravenously once with anti-Fas antibody (Jo2), we failed to determine any target organ, except the liver, responsible for the acute lethality induced by the Fas/anti-Fas antibody interaction. However, we could show the presence of Fas-mediated apoptosis in other organs aside from the liver and normal mouse strain differences in susceptibility to anti-Fas antibody. Among these strains, C3H/HeN was the most susceptible to the antibody, followed by ICR and DBA/1J. We observed Fas-mediated apoptosis in the liver, spleen, thymus, lymph nodes, Peyer's patch, intestine, skin, coagulation glands, ovary, uterus, and vagina in all 3 strains and additionally in the epididymides and seminal vesicles in the DBA/1J strain. We also demonstrated that Fas-mediated apoptosis of small lymphocytes in the mantle zone of splenic lymphatic follicles preceded that of the hepatocytes or thymic cells. Since cellular damage was most severe in the liver among all the apoptotic organs in the 3 mouse strains, liver injury induced by anti-Fas antibody is speculated to play a significant role in the death.
Insights
Anti-Fas antibody (Jo2) causes acute lethality in mice, primarily through liver injury. Susceptibility varies among mouse strains, with C3H/HeN being most vulnerable to Fas-mediated apoptosis.
Area of Science:
- Immunology
- Toxicology
- Pathology
Background:
- The Fas/anti-Fas antibody interaction is known to induce apoptosis.
- Understanding the specific organ targets and strain-dependent susceptibility is crucial for assessing toxicity.
Purpose of the Study:
- To investigate the target organs responsible for acute lethality induced by anti-Fas antibody (Jo2) in mice.
- To evaluate differences in susceptibility to anti-Fas antibody among normal mouse strains.
- To characterize the pattern of Fas-mediated apoptosis across various organs.
Main Methods:
- Histopathologic examination of multiple organs in C3H/HeN, ICR, and DBA/1J mice.
- Intravenous administration of anti-Fas antibody (Jo2).
- Assessment of Fas-mediated apoptosis in different tissues.
Main Results:
- Liver injury was identified as the primary cause of acute lethality.
- Fas-mediated apoptosis was observed in numerous organs beyond the liver, including spleen, thymus, lymph nodes, and intestines.
- Significant differences in susceptibility to anti-Fas antibody were noted, with C3H/HeN mice being most susceptible, followed by ICR and DBA/1J mice.
- Apoptosis in splenic lymphocytes preceded that in hepatocytes or thymic cells.
Conclusions:
- Anti-Fas antibody-induced liver injury plays a significant role in acute lethality.
- Mouse strain differences influence susceptibility to anti-Fas antibody-mediated toxicity.
- Fas-mediated apoptosis occurs broadly across multiple organs, not exclusively in the liver.
