Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Apr 23;26(9):3968.
doi: 10.3390/ijms26093968.

Tolerogenic Therapies in Cardiac Transplantation

Laurenz Wolner  1 , Johan William-Olsson  1 , Bruno K Podesser  1 , Andreas Zuckermann  2 , Nina Pilat  1   2
Affiliations
Review

Tolerogenic Therapies in Cardiac Transplantation

Laurenz Wolner et al. Int J Mol Sci. .

Abstract

Heart transplantation remains the gold-standard treatment for end-stage heart failure, yet long-term graft survival is hindered by chronic rejection and the morbidity and mortality caused by lifelong immunosuppression. While advances in medical and device-based therapies have reduced the overall need for transplantation, patients who ultimately require a transplant often present with more advanced disease and comorbidities. Recent advances in tolerance-inducing strategies offer promising avenues to improve allograft acceptance, while minimizing immunosuppressive toxicity. This review explores novel approaches aiming to achieve long-term immunological tolerance, including co-stimulation blockade, mixed chimerism, regulatory T-cell (Treg) therapies, thymic transplantation, and double-organ transplantation. These strategies seek to promote donor-specific unresponsiveness and mitigate chronic rejection. Additionally, expanding the donor pool remains a critical challenge in addressing organ shortages. Innovations such as ABO-incompatible heart transplantation are revolutionizing the field by increasing donor availability and accessibility. In this article, we discuss the mechanistic basis, clinical advancements, and challenges of these approaches, highlighting their potential to transform the future of heart transplantation with emphasis on clinical translation.

Keywords: heart transplantation; immune tolerance; tolerogenic therapies.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Selected biologicals blocking the co-stimulatory molecules on T-cells and antigen-presenting cells. The green box indicates approved co-stimulation blockers; yellow boxes indicate co-stimulation blockers in development. Abbreviations: APC: antigen-presenting cell, KTX: kidney transplantation, CT: clinical trial. Created in BioRender. Pilat-michalek, N. [2025] https://BioRender.com/c33c247.
Figure 2
Figure 2
Selection of therapeutic approaches for Treg therapy. Created in BioRender. Pilat-michalek, N. [2025] https://BioRender.com/mg7o6kd.
See this image and copyright information in PMC

References

    1. Lodhi S.A., Lamb K.E., Meier-Kriesche H.U. Solid organ allograft survival improvement in the United States: The long-term does not mirror the dramatic short-term success. Am. J. Transplant. 2011;11:1226–1235. doi: 10.1111/j.1600-6143.2011.03539.x. - DOI - PubMed
    1. Pierson R.N., 3rd Tolerance in heart transplantation: The Holy Grail, or an attainable goal? Heart Fail. Clin. 2007;3:17–29. doi: 10.1016/j.hfc.2007.02.005. - DOI - PubMed
    1. Unger L.W., Muckenhuber M., Mahr B., Schwarz C., Pilat N., Granofszky N., Regele H., Wekerle T. Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen. Front. Immunol. 2022;13:1060576. doi: 10.3389/fimmu.2022.1060576. - DOI - PMC - PubMed
    1. Thomson A.W., Ezzelarab M.B. A Tale of Two Pathways: Renewing the Promise of Anti-CD40L Blockade. Am. J. Transplant. 2017;17:1156–1157. doi: 10.1111/ajt.14217. - DOI - PubMed
    1. Pilat N., Wekerle T. Transplantation tolerance through mixed chimerism. Nat. Rev. Nephrol. 2010;6:594–605. doi: 10.1038/nrneph.2010.110. - DOI - PubMed

MeSH terms

Substances

LinkOut - more resources