{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:47:28Z","timestamp":1785757648941,"version":"3.56.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Mammalian target of rapamycin inhibitors (mTORi) combined with tacrolimus and prednisolone enable tacrolimus dose reduction. This study evaluated everolimus\u2013low-dose tacrolimus\u2013prednisolone (EVR-IS) versus standard myco-phenolate mofetil (MMF)\u2013tacrolimus\u2013prednisolone (MMF-IS) on effector (Teff) and regulatory T cells (Tregs) in elderly kidney transplant recipients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Blood samples were obtained before, and 12 and 24 months after transplantation in the OPTIMIZE study (EudraCT 2018-003194-10). Recipients \u2265 65 years were randomized to EVR-IS or MMF-IS. Phenotype of circulating T cells (EVR-IS N\u00a0=\u00a086; MMF-IS N\u00a0=\u00a083) was assessed by multiparameter flow cytometry including transcription factors. Exploratory immune profiling in a limited cohort of kidney transplant recipients, involved detailed characterization of function and phenotype of donor antigen-specific alloreactive and virus-specific T cells, identified by activation-induced CD137 expression using multiparameter flow cytometry. Treg function was analyzed using a suppression assay after isolation and expansion of Tregs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Effector memory T cells remained stable under EVR-IS but showed a small decline for MMF-IS. Treg frequencies increased in EVR-IS recipients (2.9% to 4.1%, P&amp;lt;0.01). Under EVR-IS, donor antigen-specific alloreactive CD4+ T cells remained stable whereas they declined under MMF-IS. Furthermore, donor antigen-specific alloreactive CD8+ T cells declined more rapidly under EVR-IS than for MMF-IS. Only under EVR-IS donor antigen-specific alloreactive Tregs (3.9% to 5.8%, P\u00a0=\u00a00.03) increased, which strongly suppressed donor antigen-specific alloreactive effector T-cell proliferation. This led to significantly higher Treg\/CD4+Teff (3-fold, P&amp;lt;0.01) and Treg\/CD8+Teff (10-fold, P\u00a0=\u00a00.01) ratios for EVR-IS at M24, respectively. Both regimens reduced polyfunctional donor antigen-specific alloreactive CD4+ T cells during the first year, while proportions of virus-specific T-cells remained unchanged.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrated that everolimus-combined with low dose tacrolimus and mycophenolate mofetil combined with standard dose of tacrolimus employ different mechanisms to effectively control the alloimmune response facilitating patient-tailored immunosuppression in elderly kidney transplant recipients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1904559","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:13:59Z","timestamp":1785755639000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Everolimus-based immunosuppression induces alloreactive regulatory T cell expansion combined with loss of alloreactive effector T cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Nicolle H. R.","family":"Litjens","sequence":"first","affiliation":[{"name":"Erasmus Medical Center (MC) Transplant Institute, Department of Internal Medicine, Division of Nephrology and Transplantation, University Medical Center Rotterdam","place":["Rotterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jip","family":"Jonker","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, University Medical Center","place":["Groningen, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariska","family":"Klepper","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center (MC) Transplant Institute, Department of Internal Medicine, Division of Nephrology and Transplantation, University Medical Center Rotterdam","place":["Rotterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederique","family":"Prevoo","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center (MC) Transplant Institute, Department of Internal Medicine, Division of Nephrology and Transplantation, University Medical Center Rotterdam","place":["Rotterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis A.","family":"Hesselink","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center (MC) Transplant Institute, Department of Internal Medicine, Division of Nephrology and Transplantation, University Medical Center Rotterdam","place":["Rotterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederike J.","family":"Bemelman","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Amsterdam University Medical Center","place":["Amsterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Azam","family":"Nurmohamed","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Amsterdam University Medical Center","place":["Amsterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan D.","family":"Van Zuilen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Medical Center Utrecht","place":["Utrecht, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan P.","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, University Medical Center","place":["Groningen, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan-Stephan F.","family":"Sanders","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, University Medical Center","place":["Groningen, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel G. 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