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Journal of Virology, January 2001, p. 799-808, Vol. 75, No. 2
Fred Hutchinson Cancer Research Center,
Seattle, Washington 98109,1 Departments
of Medicine3 and
Immunology,4 University of Washington,
and the University of Washington Regional Primate Research
Center,2 Seattle, Washington 98195
Received 22 August 2000/Accepted 18 October 2000
The in vivo persistence of gene-modified cells can be limited by
host immune responses to transgene-encoded proteins. In this study we
evaluated in a nonhuman primate model whether the administration of a
nonmyeloablative regimen consisting of low-dose total-body irradiation
with 200 cGy followed by immunosuppression with mycophenolate mofetil
and cyclosporin A for 28 and 35 days, respectively, could be used to
facilitate persistence of autologous gene-modified T cells when a
transgene-specific immune response had already been established or to
induce long-lasting tolerance in unprimed recipients. Two macaques
(Macaca nemestrina) received infusions of T cells
transduced to express either the enhanced green fluorescent protein and
neomycin phosphotransferase genes or the hygromycin phosphotransferase
and herpes simplex virus thymidine kinase genes. In the absence of
immunosuppression, both macaques developed potent class I major
histocompatibility complex-restricted CD8+ cytotoxic
T-lymphocyte (CTL) responses that rapidly eliminated the gene-modified
T cells and that persisted long term as memory CTL. Treatment with the
nonmyeloablative regimen failed to abrogate preexisting memory CTL
responses but interfered with the induction of transgene-specific CTL
and facilitated in vivo persistence of gene-modified cells in an
unprimed host. However, sustained tolerance to gene-modified T cells
was not achieved with this regimen, indicating that further
modifications will be required to permit sustained persistence of
gene-modified T cells.
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.2.799-808.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Nonmyeloablative Immunosuppressive Regimen Prolongs
In Vivo Persistence of Gene-Modified Autologous T Cells in a Nonhuman
Primate Model
*
Corresponding author. Mailing address: Fred Hutchinson
Cancer Research Center, 1100 Fairview Ave. N., D1-100, Seattle, WA 98109-1024. Phone: (206) 667-4425. Fax: (206) 667-6124. E-mail: hkiem{at}fhcrc.org.
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