Nonmyeloablative immunosuppressive regimen prolongs In vivo persistence of gene-modified autologous T cells in a nonhuman primate model
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Nonmyeloablative immunosuppressive regimen prolongs In vivo persistence of gene-modified autologous T cells in a nonhuman primate model. / Berger, C; Huang, M L; Gough, M; Greenberg, P D; Riddell, S R; Kiem, H P.
in: J VIROL, Jahrgang 75, Nr. 2, 01.2001, S. 799-808.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Nonmyeloablative immunosuppressive regimen prolongs In vivo persistence of gene-modified autologous T cells in a nonhuman primate model
AU - Berger, C
AU - Huang, M L
AU - Gough, M
AU - Greenberg, P D
AU - Riddell, S R
AU - Kiem, H P
PY - 2001/1
Y1 - 2001/1
N2 - 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.
AB - 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.
KW - Animals
KW - CD8-Positive T-Lymphocytes/immunology
KW - Cyclosporine/pharmacology
KW - Green Fluorescent Proteins
KW - Hematopoietic Stem Cell Transplantation
KW - Immunologic Memory
KW - Immunosuppression
KW - Immunosuppressive Agents/pharmacology
KW - Kanamycin Kinase/genetics
KW - Luminescent Proteins/genetics
KW - Macaca nemestrina
KW - Mycophenolic Acid/analogs & derivatives
KW - Retroviridae/genetics
KW - Simplexvirus/enzymology
KW - T-Lymphocytes/immunology
KW - Thymidine Kinase/genetics
KW - Transfection
KW - Transgenes
KW - Transplantation, Autologous
KW - Whole-Body Irradiation
U2 - 10.1128/JVI.75.2.799-808.2001
DO - 10.1128/JVI.75.2.799-808.2001
M3 - SCORING: Journal article
C2 - 11134293
VL - 75
SP - 799
EP - 808
JO - J VIROL
JF - J VIROL
SN - 0022-538X
IS - 2
ER -