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Updated: Jun 18, 2026
In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients
Published on: August 12, 2017
TGFbeta neutralization within cardiac allografts by decorin gene transfer attenuates chronic rejection
Susan M Faust1, Guanyi Lu, Sherri C Wood
1Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
Insights
Neutralizing transforming growth factor-beta (TGF-β) within cardiac allografts inhibits fibrosis and improves function. This approach preserves the beneficial systemic immunosuppression, preventing chronic allograft rejection without reversing immune tolerance.
Area of Science:
- Immunology
- Transplantation Biology
- Molecular Medicine
Background:
- Chronic allograft rejection (CR) is the primary cause of late graft loss after organ transplantation.
- Transforming growth factor-beta (TGF-β) has dual roles in transplantation, promoting immunosuppression and graft fibrosis.
- Intragraft TGF-β expression is associated with CR in mouse cardiac allograft models.
Purpose of the Study:
- To investigate the impact of intragraft TGF-β neutralization on CR, T cell responses, and allograft acceptance.
- To assess the efficacy of decorin gene transfer for inhibiting TGF-β in cardiac allografts.
- To determine if blocking TGF-β locally affects systemic immune tolerance.
Main Methods:
- Utilized a mouse vascularized cardiac allograft model.
- Employed gene transfer of decorin to neutralize intragraft TGF-β.
- Assessed graft function, interstitial fibrosis, cardiac hypertrophy, and systemic donor-reactive T cell responses.
Main Results:
- Decorin gene transfer significantly attenuated interstitial fibrosis, cardiac hypertrophy, and improved graft function.
- Intragraft TGF-β neutralization did not reverse the hyporesponsive state of systemic donor-reactive T cells.
- Allograft acceptance was improved without inducing systemic donor-specific immune responses.
Conclusions:
- Neutralizing intragraft TGF-β effectively inhibits its fibrotic effects in cardiac allografts.
- Local TGF-β inhibition preserves the systemic immunosuppressive benefits of TGF-β.
- This strategy offers a potential therapeutic approach to mitigate CR while maintaining graft tolerance.
Abstract:
Chronic allograft rejection (CR) is the leading cause of late graft failure following organ transplantation. CR is a progressive disease, characterized by deteriorating graft function, interstitial fibrosis, cardiac hypertrophy, and occlusive neointima development. TGFbeta, known for its immunosuppressive qualities, plays a beneficial role in the transplant setting by maintaining alloreactive T cells in a hyporesponsive state, but has also been implicated in promoting graft fibrosis and CR. In the mouse vascularized cardiac allograft model, transient depletion of CD4(+) cells promotes graft survival but leads to CR, which is associated with intragraft TGFbeta expression. Decorin, an extracellular matrix protein, inhibits both TGFbeta bioactivity and gene expression. In this study, gene transfer of decorin into cardiac allografts was used to assess the impact of intragraft TGFbeta neutralization on CR, systemic donor-reactive T cell responses, and allograft acceptance. Decorin gene transfer and neutralization of TGFbeta in cardiac allografts significantly attenuated interstitial fibrosis, cardiac hypertrophy, and improved graft function, but did not result in systemic donor-reactive T cell responses. Thus, donor-reactive T and B cells remained in a hyporesponsive state. These findings indicate that neutralizing intragraft TGFbeta inhibits the cytokine's fibrotic activities, but does not reverse its beneficial systemic immunosuppressive qualities.
