DNA-liposome versus adenoviral mediated gene transfer of transforming growth factorβ1 in vascularized cardiac allografts

Differential sensitivity of CD4+ and CD8+ T cells to transforming growth factorβ1

Sherri Y. Chan, Richard E Goodman, Jacqueline R. Szmuszkovicz, Blake Roessler, Ernst J. Eichwald, D. Keith Bishop

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

We have developed a model of transforming growth factor (TGF)β1 gene transfer into mouse vascularized cardiac allografts to study the use of gene transfer as an immunosuppressive therapy in transplantation. Donor hearts were perfused with either DNA-liposome complexes or adenoviral vectors that encode the active form of human TGFβ1. DNA-liposome mediated transfection prolonged allograft survival in approximately two-thirds of transplant recipients, while adenoviral delivery of TGFβ1 was not protective. Protective TGFβ1 gene transfer was associated with reduced Th1 responses and an inhibition of the alloantibody isotype switch. The protective effects of TGFβ1 gene transfer were overridden by exogenous interleukin-12 administration. Interestingly, alloreactive CD4+ and CD8+ cells exhibited distinct sensitivities to TGFβ1 gene transfer: CD4+ Th1 function was abrogated by this modality, although CD8+ Th1 function was not. Transient depletion of recipient CD8+ cells markedly prolonged the survival of grafts transfected with either DNA-liposome complexes or adenoviral vectors. Transgene expression persisted for at least 60 days, and Th1 responses were not detectable until CD8+ T cells repopulated the periphery. However, long-term transfected allografts appeared to exhibit exacerbated fibrosis and neointimal development. These manifestations of chronic rejection were absent in long-term transfected isografts, suggesting that long-term expression of active TGFβ1 alone is not sufficient to induce fibrosis of the grafts. Collectively, these data illustrate the utility of immunosuppressive gene therapy as a treatment for transplantation when combined with additional conditioning regimens. Further, they illustrate that alloreactive CD4+ and CD8+ cells may be differentially influenced by cytokine manipulation strategies.

Original languageEnglish (US)
Pages (from-to)1292-1301
Number of pages10
JournalTransplantation
Volume70
Issue number9
DOIs
StatePublished - Nov 15 2000

Fingerprint

Oncogenes
Liposomes
Allografts
T-Lymphocytes
DNA
Growth
Genes
Immunosuppressive Agents
Fibrosis
Transplantation
Isografts
Isoantibodies
Transforming Growth Factors
Graft Survival
Interleukin-12
Transgenes
Genetic Therapy
Transfection
Tissue Donors
Cytokines

ASJC Scopus subject areas

  • Transplantation

Cite this

DNA-liposome versus adenoviral mediated gene transfer of transforming growth factorβ1 in vascularized cardiac allografts : Differential sensitivity of CD4+ and CD8+ T cells to transforming growth factorβ1. / Chan, Sherri Y.; Goodman, Richard E; Szmuszkovicz, Jacqueline R.; Roessler, Blake; Eichwald, Ernst J.; Bishop, D. Keith.

In: Transplantation, Vol. 70, No. 9, 15.11.2000, p. 1292-1301.

Research output: Contribution to journalArticle

@article{11f63b6d6aa045418f08e27beb2a6b74,
title = "DNA-liposome versus adenoviral mediated gene transfer of transforming growth factorβ1 in vascularized cardiac allografts: Differential sensitivity of CD4+ and CD8+ T cells to transforming growth factorβ1",
abstract = "We have developed a model of transforming growth factor (TGF)β1 gene transfer into mouse vascularized cardiac allografts to study the use of gene transfer as an immunosuppressive therapy in transplantation. Donor hearts were perfused with either DNA-liposome complexes or adenoviral vectors that encode the active form of human TGFβ1. DNA-liposome mediated transfection prolonged allograft survival in approximately two-thirds of transplant recipients, while adenoviral delivery of TGFβ1 was not protective. Protective TGFβ1 gene transfer was associated with reduced Th1 responses and an inhibition of the alloantibody isotype switch. The protective effects of TGFβ1 gene transfer were overridden by exogenous interleukin-12 administration. Interestingly, alloreactive CD4+ and CD8+ cells exhibited distinct sensitivities to TGFβ1 gene transfer: CD4+ Th1 function was abrogated by this modality, although CD8+ Th1 function was not. Transient depletion of recipient CD8+ cells markedly prolonged the survival of grafts transfected with either DNA-liposome complexes or adenoviral vectors. Transgene expression persisted for at least 60 days, and Th1 responses were not detectable until CD8+ T cells repopulated the periphery. However, long-term transfected allografts appeared to exhibit exacerbated fibrosis and neointimal development. These manifestations of chronic rejection were absent in long-term transfected isografts, suggesting that long-term expression of active TGFβ1 alone is not sufficient to induce fibrosis of the grafts. Collectively, these data illustrate the utility of immunosuppressive gene therapy as a treatment for transplantation when combined with additional conditioning regimens. Further, they illustrate that alloreactive CD4+ and CD8+ cells may be differentially influenced by cytokine manipulation strategies.",
author = "Chan, {Sherri Y.} and Goodman, {Richard E} and Szmuszkovicz, {Jacqueline R.} and Blake Roessler and Eichwald, {Ernst J.} and Bishop, {D. Keith}",
year = "2000",
month = "11",
day = "15",
doi = "10.1097/00007890-200011150-00006",
language = "English (US)",
volume = "70",
pages = "1292--1301",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "9",

}

TY - JOUR

T1 - DNA-liposome versus adenoviral mediated gene transfer of transforming growth factorβ1 in vascularized cardiac allografts

T2 - Differential sensitivity of CD4+ and CD8+ T cells to transforming growth factorβ1

AU - Chan, Sherri Y.

AU - Goodman, Richard E

AU - Szmuszkovicz, Jacqueline R.

AU - Roessler, Blake

AU - Eichwald, Ernst J.

AU - Bishop, D. Keith

PY - 2000/11/15

Y1 - 2000/11/15

N2 - We have developed a model of transforming growth factor (TGF)β1 gene transfer into mouse vascularized cardiac allografts to study the use of gene transfer as an immunosuppressive therapy in transplantation. Donor hearts were perfused with either DNA-liposome complexes or adenoviral vectors that encode the active form of human TGFβ1. DNA-liposome mediated transfection prolonged allograft survival in approximately two-thirds of transplant recipients, while adenoviral delivery of TGFβ1 was not protective. Protective TGFβ1 gene transfer was associated with reduced Th1 responses and an inhibition of the alloantibody isotype switch. The protective effects of TGFβ1 gene transfer were overridden by exogenous interleukin-12 administration. Interestingly, alloreactive CD4+ and CD8+ cells exhibited distinct sensitivities to TGFβ1 gene transfer: CD4+ Th1 function was abrogated by this modality, although CD8+ Th1 function was not. Transient depletion of recipient CD8+ cells markedly prolonged the survival of grafts transfected with either DNA-liposome complexes or adenoviral vectors. Transgene expression persisted for at least 60 days, and Th1 responses were not detectable until CD8+ T cells repopulated the periphery. However, long-term transfected allografts appeared to exhibit exacerbated fibrosis and neointimal development. These manifestations of chronic rejection were absent in long-term transfected isografts, suggesting that long-term expression of active TGFβ1 alone is not sufficient to induce fibrosis of the grafts. Collectively, these data illustrate the utility of immunosuppressive gene therapy as a treatment for transplantation when combined with additional conditioning regimens. Further, they illustrate that alloreactive CD4+ and CD8+ cells may be differentially influenced by cytokine manipulation strategies.

AB - We have developed a model of transforming growth factor (TGF)β1 gene transfer into mouse vascularized cardiac allografts to study the use of gene transfer as an immunosuppressive therapy in transplantation. Donor hearts were perfused with either DNA-liposome complexes or adenoviral vectors that encode the active form of human TGFβ1. DNA-liposome mediated transfection prolonged allograft survival in approximately two-thirds of transplant recipients, while adenoviral delivery of TGFβ1 was not protective. Protective TGFβ1 gene transfer was associated with reduced Th1 responses and an inhibition of the alloantibody isotype switch. The protective effects of TGFβ1 gene transfer were overridden by exogenous interleukin-12 administration. Interestingly, alloreactive CD4+ and CD8+ cells exhibited distinct sensitivities to TGFβ1 gene transfer: CD4+ Th1 function was abrogated by this modality, although CD8+ Th1 function was not. Transient depletion of recipient CD8+ cells markedly prolonged the survival of grafts transfected with either DNA-liposome complexes or adenoviral vectors. Transgene expression persisted for at least 60 days, and Th1 responses were not detectable until CD8+ T cells repopulated the periphery. However, long-term transfected allografts appeared to exhibit exacerbated fibrosis and neointimal development. These manifestations of chronic rejection were absent in long-term transfected isografts, suggesting that long-term expression of active TGFβ1 alone is not sufficient to induce fibrosis of the grafts. Collectively, these data illustrate the utility of immunosuppressive gene therapy as a treatment for transplantation when combined with additional conditioning regimens. Further, they illustrate that alloreactive CD4+ and CD8+ cells may be differentially influenced by cytokine manipulation strategies.

UR - http://www.scopus.com/inward/record.url?scp=0034669333&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034669333&partnerID=8YFLogxK

U2 - 10.1097/00007890-200011150-00006

DO - 10.1097/00007890-200011150-00006

M3 - Article

VL - 70

SP - 1292

EP - 1301

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 9

ER -