Prolonged survival of human hepatocarcinoma cells in the liver of newborn C57BL/6 mice and resulting cellular xenorejection, especially the activation of hepatic natural killer T cells.
OBJECTIVE
To investigate the fate of human hepatocellular carcinoma (HCC) in the livers of newborn mice and the resulting cellular rejection.


METHODS
Two HCC cell lines (HepG2 and HCCLM3) labeled with DMAHAS were orthotopically transplanted to newborn and adult mice with or without low-dose cyclosporin A (CsA) treatment (10 mg/kg). The fate of tumor xenografts was examined and the resulting cellular response was investigated.


RESULTS
Tumor xenografts survived in newborn mice for > 4 weeks, with a delayed lymphocyte infiltration mediated by CD4+ T, CD8+ T and NK1.1+ cells. In contrast, the xenografts survived in adults < 8-10 days with an acute cellular rejection by CD8+T cells, NK1.1+ cells, macrophages or neutrophils. Orthotopic transplantation of human HCC xenografts elicited a strong cytotoxic response in newborn mice (p < 0.05), and selective T/NK1.1+ cell deletion in vitro suggested that such effector cells were mainly CD8+ T cells. Moreover, tumor xenografts induced a rapid activation of hepatic natural killer T (NKT) cells in both newborn and adult mice with enhanced secretion of IL-4 and IFN-gamma in serum and subsequent NKT-like cytotoxicity. The rapid activation of NKT cells could be efficiently suppressed by low-dose CsA treatment, possibly in a CD1d-independent manner.


CONCLUSIONS
Our data suggest that the livers of newborn mice were more suitable for the survival of xenografts than those of adult mice. Cell-mediated tumor xenorejection in newborn mice was different from that in adults, and hepatic NKT cells may play an important role in early tumor xenorejection.
Laboratory for Developmental Immunology, School of Life Science, Shandong University, Shenyang, People's Republic of China.
Xiumin
X
Du
Zengliang
Z
Bai
Jingping
J
Zhang
Lanlan
L
Liu
Ying
Y
Han
Ze
Z
Wang
Tianxiao
T
Huan
Baojun
B
Wu
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D055610:Antigens, CD1d / Q000276:immunology; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology; D002470:Cell Survival; D016572:Cyclosporine / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007111:Immunity, Cellular; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology*; D009368:Neoplasm Transplantation; D013154:Spleen / Q000276:immunology; D013997:Time Factors; D014183:Transplantation, Heterologous; D019139:Tumor Escape / Q000187:drug effects
D055610:Antigens, CD1d; D017252:CD3 Complex; C526879:Cd1d1 protein, mouse; D007166:Immunosuppressive Agents; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine