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PLoS One. 2012;7(6):e38491.
An improved protocol for efcient engraftment
in NOD/LTSZ-SCIDIL-2Rγnull mice allows HIV
replication and development of anti-HIV immune
responses.
Singh M, Singh P, Gaudray G, Musumeci L, Thielen C, Vaira D, Vandergeeten C, Delacroix L,
Van Gulck E, Vanham G, de Leval L, Rahmouni S, Moutschen M.
Abstract
Cord blood hematopoietic progenitor cells (CB-HPCs) transplanted immunodefcient NOD/
LtsZ-scidIL2Rγ(null) (NSG) and NOD/SCID/IL2Rγ(null) (NOG) mice need efcient human cell
engraftment for long-term HIV-1 replication studies. Total body irradiation (TBI) is a classical
myeloablation regimen used to improve engraftment levels of human cells in these huma-
nized mice. Some recent reports suggest the use of busulfan as a myeloablation regimen to
transplant HPCs in neonatal and adult NSG mice. In the present study, we further amelio-
rated the busulfan myeloablation regimen with fresh CB-CD34+cell transplantation in 3-4
week old NSG mice. In this CB-CD34+transplanted NSG mice engraftment efciency of
human CD45+cell is over 90% in peripheral blood. Optimal engraftment promoted early and
increased CD3+T cell levels, with better lymphoid tissue development and prolonged human
cell chimerism over 300 days. These humanized NSG mice have shown long-lasting viremia
after HIV-1JRCSF and HIV-1Bal inoculation through intravenous and rectal routes. We also
saw a gradual decline of the CD4+T cell count, widespread immune activation, up-regulation
of infammation marker and microbial translocation after HIV-1 infection. Humanized NSG
mice reconstituted according to our new protocol produced, moderate cellular and humoral
immune responses to HIV-1 postinfection. We believe that NSG mice reconstituted accor-
ding to our easy to use protocol will provide a better in vivo model for HIV-1 replication and
anti-HIV-1 therapy trials.
PLoS One. 2012;7(12):e52564.
Imatinib and nilotinib inhibit hematopoietic
progenitor cell growth, but do not prevent
adhesion, migration and engraftment of human cord
blood CD34+ cells.
Belle L, Bruck F, Foguenne J, Gothot A, Beguin Y, Baron F, Briquet A.
Abstract
BACKGROUND:
The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management
of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known
to inhibit the tyrosine kinase of the stem cell factor receptor, c-Kit. Nilotinib is 30 times more
potent than imatinib towards BCR-ABL
in vitro
. Studies in healthy volunteers and patients
with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that thera-
peutic doses of nilotinib deliver drug levels similar to those of imatinib. The aim of this study
was to compare the inhibitory efects of imatinib and nilotinib on proliferation, diferentia-
tion, adhesion, migration and engraftment capacities of human cord blood CD34(+) cells.
DESIGN AND METHODS:
After a 48-hour cell culture with or without TKIs, CFC, LTC-IC, migration, adhesion and cell
cycle analysis were performed. In a second time, the impact of these TKIs on engraftment was
assessed in a xenotransplantation model using NOD/SCID/IL-2Rγ (null) mice.
RESULTS:
TKIs did not afect LTC-IC frequencies despite
in vitro
inhibition of CFC formation due to
inhibition of CD34(+) cell cycle entry. Adhesion of CD34(+) cells to retronectin was reduced
in the presence of either imatinib or nilotinib but only at high concentrations. Migration
through a SDF-1α gradient was not changed by cell culture in the presence of TKIs. Finally,
bone marrow cellularity and human chimerism were not afected by daily doses of imatinib
and nilotinib in a xenogenic transplantation model. No signifcant diference was seen between
TKIs given the equivalent afnity of imatinib and nilotinib for KIT.
CONCLUSIONS:
These data suggest that combining non-myeloablative conditioning regimen with TKIs starting
the day of the transplantation could be safe.