Fas Ligand-dependent and -independent mechanisms of toxicity induced by T cell lymphomas in lymphoid organs and in the liver.

Abstract

In the current study, we investigated the effect of growth of FasL(+) tumors in vivo on the functions of peripheral lymphoid organs and the liver. Injection of FasL(+) LSA tumor cells into syngeneic C57BL/6 wild-type mice but not C57BL/6 lpr/lpr (Fas-deficient) mice caused apoptosis in splenocytes. Spleen cells expressing CD3, CD4, CD8, CD19, Mac-3, and CD44 were all susceptible to tumor-induced apoptosis. Also, activated T cells were more sensitive to apoptosis induced by LSA tumor cell lysate when compared to naïve T cells. In contrast, anti-Fas Abs (Jo2) induced apoptosis in only activated but not naïve T cells. When the LSA tumor-bearing mice were injected with a superantigen (SEA), these mice showed a significant decrease in the expansion of SEA-reactive Vbeta3(+) and Vbeta11(+) T cells. When injected into syngeneic mice, the FasL(+) LSA tumor cells caused hepatotoxicity, as indicated by an increase in serum aspartate aminotransferase (AST) levels. Interestingly, Fas-deficient C57BL/6 lpr/lpr mice also showed significant AST levels in the serum following LSA tumor growth. Moreover, hepatocytes isolated from C57BL/6 wild-type and C57BL/6 lpr/lpr mice were equally susceptible to apoptosis induced by LSA tumor cell lysate in vitro. Using cDNA array, LSA tumor cells were found to express several cytokine genes including IL-2, IL-7, IL-11, IL-13, IL-16, lymphotoxin beta, and tumor necrosis factor beta. Together, these data suggested that, in mice bearing FasL(+) LSA tumor, the immunotoxicity is FasL-based, whereas the hepatotoxicity, at least in part, may be FasL-independent.

• Authors: Catherine Lombard, Robert J McKallip, Philip B Hylemon, Prakash S Nagarkatti, Mitzi Nagarkatti
• Journal: Clinical immunology (Orlando, Fla.) (Clin Immunol) Vol. 109 Issue 2 Pg. 144-53 (Nov 2003) ISSN: 1521-6616 [Print] United States
• PMID: 14597213 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Fas Ligand Protein
• Fasl protein, mouse
• Membrane Glycoproteins
• Superantigens
• Aspartate Aminotransferases

Topics

• Animals
• Apoptosis (immunology)
• Aspartate Aminotransferases (blood)
• Cell Division
• Cytokines (genetics, immunology)
• Fas Ligand Protein
• Female
• Flow Cytometry
• Hepatocytes (immunology)
• In Situ Nick-End Labeling
• Liver (immunology, pathology)
• Lymphoma, T-Cell (immunology, pathology)
• Membrane Glycoproteins (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Inbred MRL lpr
• Neoplasms, Experimental (immunology, pathology)
• Oligonucleotide Array Sequence Analysis
• Spleen (immunology, pathology)
• Superantigens (immunology)
• T-Lymphocytes (immunology)