Antigen-dependent transgene expression in kidney transplantation: a novel approach using gene-engineered T lymphocytes.
So far, gene therapy in transplantation mainly focuses on the expression of therapeutic proteins in the graft itself. Insufficient transfection and inflammatory responses that are due to the immunogenicity of multiple vector systems are often limiting factors in these approaches. The potential of genetically modified T lymphocytes was investigated as a delivery system for therapeutic transgenes to transplanted organs as a way to circumvent immunogenicity and efficiency problems in a rat transplant model. Gene-engineering of alloantigen-specific rat T cell lines was performed by using a Moloney murine leukemia virus (MoMuLV)-based enhanced green fluorescence protein (EGFP) encoding retroviral transduction system. The ex vivo gene-modified lymphocytes were adoptively transferred into syngeneic rats carrying allogeneic, syngeneic, or third party kidneys. Homing behavior, activation level, and transgene expression of the adoptively given cells were monitored. The T(EGFP) lymphocytes infiltrated the transplanted kidneys in an antigen-specific manner. High numbers of alloantigen-specific T lymphocytes accumulated exclusively in allografts but not in syngeneic or third party grafts. Flow cytometric analysis revealed that only T(EGFP) lymphocytes found in allografts had an activated phenotype that resulted in higher transgene expression. Alloantigen-specific homing, activation, and transgene expression are important prerequisites for the guarantee of localized delivery and expression of transgenic proteins by gene-engineered T lymphocytes. Antigen-specific gene-targeting strategies using ex vivo modified T lymphocytes with donor specificity are a novel approach to the delivery of therapeutic transgenes in transplantation.
Hammer
Markus H
MH
*Institute of Medical Immunology, Charité, Humboldt-University, Berlin, Germany; Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany; Department of Neuroimmunology, Max-Planck Institute for Neurobiology, Martinsried, Germany.
Schröder
Grit
G
*Institute of Medical Immunology, Charité, Humboldt-University, Berlin, Germany; Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany; Department of Neuroimmunology, Max-Planck Institute for Neurobiology, Martinsried, Germany.
Risch
Kirsten
K
*Institute of Medical Immunology, Charité, Humboldt-University, Berlin, Germany; Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany; Department of Neuroimmunology, Max-Planck Institute for Neurobiology, Martinsried, Germany.
Flügel
Alexander
A
*Institute of Medical Immunology, Charité, Humboldt-University, Berlin, Germany; Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany; Department of Neuroimmunology, Max-Planck Institute for Neurobiology, Martinsried, Germany.
Volk
Hans-Dieter
HD
*Institute of Medical Immunology, Charité, Humboldt-University, Berlin, Germany; Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany; Department of Neuroimmunology, Max-Planck Institute for Neurobiology, Martinsried, Germany.
Lehmann
Manfred
M
*Institute of Medical Immunology, Charité, Humboldt-University, Berlin, Germany; Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany; Department of Neuroimmunology, Max-Planck Institute for Neurobiology, Martinsried, Germany.
Ritter
Thomas
T
*Institute of Medical Immunology, Charité, Humboldt-University, Berlin, Germany; Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany; Department of Neuroimmunology, Max-Planck Institute for Neurobiology, Martinsried, Germany.
D019264:Adoptive Transfer; D000818:Animals; D016922:Cellular Senescence / Q000502:physiology; D015870:Gene Expression / Q000502:physiology*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005818:Genetic Engineering / Q000379:methods*; D049452:Green Fluorescent Proteins; D007519:Isoantigens / Q000502:physiology*; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D019076:Transgenes / Q000502:physiology*
D007519:Isoantigens; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins