A Disseminated Human Neuroblastoma Model in SCID Mice

Author(s):  
Claudia Gottstein ◽  
Gisela Schön ◽  
Samir Tawadros ◽  
Frank Berthold ◽  
Andreas Engert
2006 ◽  
Vol 80 (3) ◽  
pp. 1427-1439 ◽  
Author(s):  
Alexander A. Rumyantsev ◽  
Brian R. Murphy ◽  
Alexander G. Pletnev

ABSTRACT Langat virus (LGT), the naturally attenuated member of the tick-borne encephalitis virus (TBEV) complex, was tested extensively in clinical trials as a live TBEV vaccine and was found to induce a protective, durable immune response; however, it retained a low residual neuroinvasiveness in mice and humans. In order to ablate or reduce this property, LGT mutants that produced a small plaque size or temperature-sensitive (ts) phenotype in Vero cells were generated using 5-fluorouracil. One of these ts mutants, clone E5-104, exhibited a more than 103-fold reduction in replication at the permissive temperature in both mouse and human neuroblastoma cells and lacked detectable neuroinvasiveness for highly sensitive immunodeficient mice. The E5-104 mutant possessed five amino acid substitutions in the structural protein E and one change in each of the nonstructural proteins NS3 and NS5. Using reverse genetics, we demonstrated that a Lys46→Glu substitution in NS3 as well as a single Lys315→Glu change in E significantly impaired the growth of LGT in neuroblastoma cells and reduced its peripheral neurovirulence for SCID mice. This study and our previous experience with chimeric flaviviruses indicated that a decrease in viral replication in neuroblastoma cells might serve as a predictor of in vivo attenuation of the neurotropic flaviviruses. The combination of seven mutations identified in the nonneuroinvasive E5-104 mutant provided a useful foundation for further development of a live attenuated TBEV vaccine. An evaluation of the complete sequence of virus recovered from brain of SCID mice inoculated with LGT mutants identified sites in the LGT genome that promoted neurovirulence/neuroinvasiveness.


2006 ◽  
Vol 78 (2) ◽  
pp. 129-134 ◽  
Author(s):  
Bhupesh Parashar ◽  
Bridget Shafit-Zagardo
Keyword(s):  
Low Dose ◽  

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4325-4332 ◽  
Author(s):  
F Arguello ◽  
JA Sterry ◽  
YZ Zhao ◽  
MR Alexander ◽  
RH Shoemaker ◽  
...  

We have investigated human lactate dehydrogenase (LDH) isoenzymes and human nuclear matrix protein 41/7 (NMP 41/7) as potential serologic markers to monitor the course of human leukemia in severe combined immunodeficient (SCID) mice. Following the transplantation of 10(6) human acute lymphoblastic leukemia (ALL) Nalm-6 cells, human specific LDH isoenzymes were measurable in the serum of SCID mice as early as 7 days after transplantation, although serum total LDH increased in some animals as early as 5 days after transplantation. Human NMP 41/7 was measurable in all animals at day 15 after leukemia cell injection. Serum levels of total LDH, human specific LDH and NMP 41/7 increased progressively over time, reaching total LDH levels as high as 50,000 U/L at day 25 after transplantation. To determine whether the levels of LDH and NMP 41/7 in serum were a reflection of human tumor burden, we studied these serologic markers in SCID mice bearing measurable subcutaneous human neuroblastoma tumors, or compared the serum levels of these markers with the number of human leukemia CD10+ cells in the bone marrow of the SCID mice. The serum levels of total LDH, human specific LDH isoenzymes, and NMP 41/7 correlated well with tumor burden, and they drastically decreased or disappeared from serum after the human leukemia or neuroblastoma cells were selectively killed with a single intravenous (IV) injection of 1 to 3 micrograms diphtheria toxin (DT) (the cellular receptor for DT is present on human cells, but not on mouse cells). Paraplegic mice with central nervous system leukemia completely recovered after DT treatment. We conclude that measurements of serum levels of total LDH, human LDH isoenzymes, and NMP 41/7 are sensitive, quantitative, rapid, and easy to perform serologic methods useful to monitor the engraftment, progression, and treatment response of human leukemia in SCID mice.


2007 ◽  
Vol 56 (11) ◽  
pp. 1733-1742 ◽  
Author(s):  
Roberta Castriconi ◽  
Alessandra Dondero ◽  
Michele Cilli ◽  
Emanuela Ognio ◽  
Annalisa Pezzolo ◽  
...  

1996 ◽  
Vol 180 (4) ◽  
pp. 415-422 ◽  
Author(s):  
MAURO PIACENTINI ◽  
LUCIA PIREDDA ◽  
DONATELLA STARACE ◽  
MARGHERITA ANNICCHIARICO-PETRUZZELLI ◽  
MAURIZIO MATTEI ◽  
...  

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