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Blood, 1 April 2001, Vol. 97, No. 7, pp. 1951-1959
GENE THERAPY
Induction of cytotoxic T lymphocyte and antibody responses to
enhanced green fluorescent protein following transplantation of
transduced CD34+ hematopoietic cells
Michael Rosenzweig,
Michelle Connole,
Rhona Glickman,
Soon-Pak Shinji Yue,
Bradley Noren,
MaryAnn DeMaria, and
R. Paul Johnson
From the New England Regional Primate Research Center,
Harvard Medical School, Southborough, MA; and Partners AIDS Research
Center and Infectious Disease Unit, Massachusetts General Hospital,
Harvard Medical School, Charlestown, MA.
Genetic modification of hematopoietic stem cells often results in
the expression of foreign proteins in pluripotent progenitor cells and
their progeny. However, the potential for products of foreign genes
introduced into hematopoietic stem cells to induce host immune
responses is not well understood. Gene marking and induction of immune
responses to enhanced green fluorescent protein (eGFP) were examined in
rhesus macaques that underwent nonmyeloablative irradiation followed by
infusions of CD34+ bone marrow cells transduced with a
retroviral vector expressing eGFP. CD34+ cells were
obtained from untreated animals or from animals treated with
recombinant human granulocyte colony-stimulating factor (G-CSF) alone
or G-CSF and recombinant human stem cell factor. Levels of
eGFP-expressing cells detected by flow cytometry peaked at 0.1% to
0.5% of all leukocytes 1 to 4 weeks after transplantation. Proviral
DNA was detected in 0% to 17% of bone marrow-derived colony-forming
units at periods of 5 to 18 weeks after transplantation. However, 5 of
6 animals studied demonstrated a vigorous eGFP-specific cytotoxic T
lymphocyte (CTL) response that was associated with a loss of
genetically modified cells in peripheral blood, as demonstrated by both
flow cytometry and polymerase chain reaction. The eGFP-specific CTL
responses were MHC-restricted, mediated by CD8+
lymphocytes, and directed against multiple epitopes. eGFP-specific CTLs
were able to efficiently lyse autologous CD34+ cells
expressing eGFP. Antibody responses to eGFP were detected in 3 of 6 animals. These data document the potential for foreign proteins
expressed in CD34+ hematopoietic cells and their progeny to
induce antibody and CTL responses in the setting of a clinically
applicable transplantation protocol.
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