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Blood, 15 January 2002, Vol. 99, No. 2, pp. 399-408
PLENARY PAPER
Targeting transgene expression to antigen-presenting cells
derived from lentivirus-transduced engrafting human hematopoietic
stem/progenitor cells
Yan Cui,
Jonathan Golob,
Erin Kelleher,
Zhaohui Ye,
Drew Pardoll, and
Linzhao Cheng
From the Division of Immunology and Hematopoiesis,
Johns Hopkins Oncology Center, Johns Hopkins University, Baltimore, MD.
Hematopoietic stem cells (HSCs) represent an important target for
the treatment of various blood disorders. As the source of critical
cells within the immune system, genetic modification of HSCs can also
be used to modulate immune responses. The effectiveness of HSC-mediated
gene therapy largely depends on efficient gene delivery into long-term
repopulating progenitors and targeted transgene expression in an
appropriate progeny of the transduced pluripotent HSCs.
Self-inactivating (SIN) lentiviral vectors have been demonstrated to be
capable of transducing mitotically inactive cells, including HSCs, and
accommodating a nonviral promoter to control the transgene expression
in transduced cells. In this study, we constructed 2 SIN lentiviral
vectors, EF.GFP and DR.GFP, to express the green fluorescent protein
(GFP) gene controlled solely by the promoter of either a housekeeping
gene EF-1 or the human HLA-DR gene, which is selectively
expressed in antigen-presenting cells (APCs). We demonstrated that both
vectors efficiently transduced human pluripotent CD34+
cells capable of engrafting nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. When the EF.GFP vector was used, constitutive high-level GFP expression was obtained in all the human
HSC progeny detectable in NOD/SCID mice and in subsequent in vitro
differentiation assays, indicating that engrafting human HSCs have been
transduced. In contrast, the DR.GFP vector mediated transgene
expression specifically in human HLA-DR+ cells and highly
in differentiated dendritic cells (DCs), which are critical in
regulating immunity. Furthermore, human DCs derived from transduced and
engrafted human cells potently stimulated allogeneic T-cell
proliferation. This study demonstrated successful targeting of
transgene expression to APCs/DCs after stable gene transduction of
pluripotent HSCs.
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