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
. 2019 Apr;16(4):324-333.
doi: 10.1038/s41423-019-0203-7. Epub 2019 Feb 13.

The pursuit of transplantation tolerance: new mechanistic insights

Pawan K Gupta  1 , Christine M McIntosh  1 , Anita S Chong  2 , Maria-Luisa Alegre  3
Affiliations

The pursuit of transplantation tolerance: new mechanistic insights

Pawan K Gupta et al. Cell Mol Immunol. 2019 Apr.

Abstract

Donor-specific transplantation tolerance that enables weaning from immunosuppressive drugs but retains immune competence to non-graft antigens has been a lasting pursuit since the discovery of neonatal tolerance. More recently, efforts have been devoted not only to understanding how transplantation tolerance can be induced but also the mechanisms necessary to maintain it as well as how inflammatory exposure challenges its durability. This review focuses on recent advances regarding key peripheral mechanisms of T cell tolerance, with the underlying hypothesis that a combination of several of these mechanisms may afford a more robust and durable tolerance and that a better understanding of these individual pathways may permit longitudinal tracking of tolerance following clinical transplantation to serve as biomarkers. This review may enable a personalized assessment of the degree of tolerance in individual patients and the opportunity to strengthen the robustness of peripheral tolerance.

Keywords: T cell dysfunction; TCR avidity; Treg; tolerance.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Mechanisms of T cell tolerance associated with transplantation tolerance. Following transplantation, naïve graft-reactive Tconvs expand, with preferential accumulation of T cell clones with higher avidity for alloantigens, and persistence of these clones into the memory phase of the alloresponse. By contrast, following a tolerogenic regimen, graft-reactive T cells undergo abortive proliferation, an event that can be Treg-dependent or -independent. This leads to the accumulation of fewer alloreactive T cell clones of lower avidity for alloantigen. The lower avidity profile persists during the maintenance phase of tolerance, with T cells of some but not all specificities constrained by Tregs. In addition, alloreactive T cells overexpress inhibitory receptors and become dysfunctional, resembling exhausted or anergic T cells, and they can sometimes recover function upon blockade of the inhibitory receptors. Bregs may also contribute to the suppression of alloreactivity, although the specific Tconv functions inhibited and at what phases and location of the alloresponse remain to be clarified
Fig. 2
Fig. 2
Tolerance is a dynamic state. Transplantation tolerance can exist at different levels of robustness depending on the redundancy of mechanisms of T cell tolerance achieved by the tolerogenic regimen, and the degree of robustness may vary over time. A robust tolerance might be more resistant to inflammatory challenges, but tolerance can be lost or eroded following infection, presumably because of a reduction in the quantity or quality of T cell mechanisms of tolerance. Some mechanisms of tolerance can be restored after the infection is cleared, enabling the acceptance of second donor-matched allografts, though the restored tolerance may be less robust after compared with before infection
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Brouard S, et al. The natural history of clinical operational tolerance after kidney transplantation through twenty-seven cases. Am. J. Transplant. 2012;12:3296–3307. - PubMed
    1. Kawai T, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N. Engl. J. Med. 2008;358:353–361. - PMC - PubMed
    1. Scandling JD, et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N. Engl. J. Med. 2008;358:362–368. - PubMed
    1. Leventhal J, et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci. Transl. Med. 2012;4:124ra128. - PMC - PubMed
    1. Kawai T, et al. Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression. Am. J. Transplant. 2014;14:1599–1611. - PMC - PubMed

MeSH terms