5.2.3 The Non-obese Diabetic/Severe Combine Immunodeficient (NOD/SCID) Mouse
To overcome the problem of low transplant success rate in SCID mice, researchers combined the SCID background mice with a non-obese diabetic (NOD) strain to create a mice strain with more severe immunodeficiency(Prochazka, Gaskins, Shultz & Leiter, 1992) that provided a supportive microenvironment for normal and malignant human hematopoietic cells. NOD/SCID mice lack of functional T or B cells, and the activities of NK cells and macrophages are reduced(Nagamoto et al., 2015), a variety of tumor cells can be implanted, immune rejection and graft-versus-host disease are less likely to occur. Therefore, NOD/SCID mice have gradually become a useful tool for hematological experimental research.
Researchers have made a breakthrough through the NOD/SCID ALL model and found that a shorter ”time to leukemia (TTL)”, that is, the time from transplantation to the appearance of leukemia is closely related to the high risk of early relapse. The proliferation of neonatal ALL cells transplanted into NOD/SCID mice has predictive value for patient prognosis, thus determining an independent prognostic factor(Meyer et al., 2011). TTLshort means TTL is less than 10 weeks, and longer time periods are classified as TTLlong. TTLshort identifies patients with early relapse, while TTLlong relapse-free survival is as high as 100%. The NOD/SCID ALL model provides a powerful tool for identifying prognostic factors in acute leukemia at the cellular and molecular levels, thus providing a rational target for therapeutic strategies. The intact apoptotic body function reflected by a positive Cytochrome c-related activation of caspase-3 (CRAC positive) is closely associated with long-term implantation of NOD/SCID (TTLLong) in primary leukemia cells and a good prognosis. The complete formation and function of apoptotic bodies means that the time of NOD/SCID implantation is prolonged, the treatment response is good, the prognosis is good, and the patient survives without recurrence(Queudeville et al., 2012). To determine disease prognostic factors, the NOD/SCID mouse model has also played an important role in exploring novel drug targets. ATLL is an aggressive disease that is highly resistant to chemotherapy. Due to the high expression of KU70 in Jurkat cells, the researchers injected Jurkat cells which knocked out of the KU70 gene into NOD/SCID mice, discovered that KU70 may be a new target for ATLL treatment and help to overcome chemo-resistance(Yu, Li, Wang, Zhang, Xu & Liang, 2018). Another xenotransplantation method is to extract hematopoietic progenitor and stem cells (HP/HSCs) from patients or mice, transduce the cells through reverse transcription or lentivirus, and then transplant them into the recipient. Researchers transplanted CD34+ hematopoietic progenitor cells and stem cells (CD34+HP/HSCs) from patients infected with HTLV-1 into NOD/SCID mice, which specifically developed CD4+T-cell lymphomas similar to ATLL, and increased proliferation of virus-infected human stem cells (CD34+CD38-) in mouse bone marrow was observed. This model provides an important tool for identifying the molecular mechanism of the occurrence and development of leukemia/lymphoma, exploring potential therapeutic targets for inhibiting tumor development and evaluating the role of HTLV-1 helper genes in the pathogenesis of the virus(Banerjee et al., 2010).
NOD/SCID mice are host that are more receptive to the proliferation of human leukemia, however, the high transplantation rate of T-ALL cells suggests that this model fails to identify risk groups, and the researchers found that human-derived T-ALL cells appear to be more readily transplanted in NOD/SCID mice, suggesting that this model may be more useful than SCID mice in studying the biology and treatment of T-ALL(Steele et al., 1997). NOD/SCID mice have lower immune function and higher tumor formation rate. More importantly, this model retains the morphological, phenotypic and genotypic characteristics of ALL donors(Bonnet & Dick, 1997). However, this mice strain will also have “leakiness”. Due to the development of thymic lymphoma and the recovery of NK cell activity, it cannot be implanted for a long time, and usually the implantation time cannot exceed 8.5 months(Shultz et al., 1995).