Differing effects of rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant recipients
Open accessAbstract
In a cross-sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T-regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg-specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty-eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =-0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =-0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long-term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.
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In human patients, tacrolimus impaired Tregs proliferation, function, and phenotype, while rapamycin had beneficial effects on Tregs.
“another study in human patients found that tacrolimus impaired Tregs proliferation, function, and phenotype, while rapamycin had bene fi cial effects on Tregs (61).”
From A versatile toolkit for overcoming AAV immunity (2022) · cites this paper as [61]
Ciclosporin and tacrolimus were found to inhibit Treg proliferation and activity in vitro, and similar effects were observed in tacrolimus-treated allograft patients ex vivo.
“Ciclosporin and tacrolimus were found to inhibit Treg proliferation and activity in vitro (79), and similar effects were observed in tacrolimus-treated allograft patients ex vivo (80); this could be detrimental in inhibiting the development of peripheral tolerance following rAAV administration.”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [80]
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- Authors
- Akimova, T., Kamath, B. M., Goebel, J. W., Meyers, K. E. C., Rand, E. B., Hawkins, A., Levine, M. H., Bucuvalas, J. C., & Hancock, W. W.
- Affiliations
- Children's Hospital of Philadelphia (US)
- University of Toronto (CA)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Hancock, W.W.
- ORCID
- Venue
- American Journal of Transplantation
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 12
- Issue
- 12
- Pages
- 3449-3461
- ISSN
- 1600-6135 (ISSN-L)
- PMC
- PMC3513508
- OpenAlex
- W1495880776
- Cited by
- 126
- References
- 30
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 9 · 2023: 11 · 2022: 11 · 2021: 9 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 17 · 2016: 14 · 2015: 9 · 2014: 13 · 2013: 3 · 2012: 1
- FWCI
- 6.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Transplantation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5ul1rr026314-03)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK092282, RC1DK087270, KO8 1K08DK092282)
- National Center for Research Resources (UL1-RR026314)
- Topics
- Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- rapamycin, calcineurin inhibitors, regulatory T cells, pediatric liver transplantation, pediatric kidney transplantation, immunosuppression, CTLA-4, CD127, Treg suppressive function, DNA methylation, allograft tolerance
- MeSH terms
- Adolescent, Child, Cross-Sectional Studies, Female, Follow-Up Studies, Graft Rejection, Humans, Immunosuppressive Agents, Leukocytes, Mononuclear, Male, Prognosis, Transplantation, Homologous, Case-Control Studies, Kidney Transplantation, Liver Transplantation, Calcineurin, Sirolimus, T-Lymphocytes, Regulatory, Forkhead Transcription Factors
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