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).