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.

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@article{1e638f30c8d3447c9dcffaddd91c6c11,
title = "Nonmyeloablative immunosuppressive regimen prolongs In vivo persistence of gene-modified autologous T cells in a nonhuman primate model",
abstract = "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.",
keywords = "Animals, CD8-Positive T-Lymphocytes/immunology, Cyclosporine/pharmacology, Green Fluorescent Proteins, Hematopoietic Stem Cell Transplantation, Immunologic Memory, Immunosuppression, Immunosuppressive Agents/pharmacology, Kanamycin Kinase/genetics, Luminescent Proteins/genetics, Macaca nemestrina, Mycophenolic Acid/analogs & derivatives, Retroviridae/genetics, Simplexvirus/enzymology, T-Lymphocytes/immunology, Thymidine Kinase/genetics, Transfection, Transgenes, Transplantation, Autologous, Whole-Body Irradiation",
author = "C Berger and Huang, {M L} and M Gough and Greenberg, {P D} and Riddell, {S R} and Kiem, {H P}",
year = "2001",
month = jan,
doi = "10.1128/JVI.75.2.799-808.2001",
language = "English",
volume = "75",
pages = "799--808",
journal = "J VIROL",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "2",

}

RIS

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 -