title: Oscillatory mTOR inhibition and Treg increase in kidney transplantation.
abstract: Intracellular metabolic pathways dependent upon the mammalian target of rapamycin (mTOR) play a key role in immune-tolerance control. In this study, we focused on long-term mTOR-dependent immune-modulating effects in kidney transplant recipients undergoing conversion from calcineurin inhibitors (CNI) to mTOR inhibitors (everolimus) in a 1-year follow-up. The conversion to everolimus is associated with a decrease of neutrophils and of CD8(+) T cells. In addition, we observed a reduced production of interferon (IFN)-γ by CD8(+) T cells and of interleukin (IL)-17 by CD4(+) T lymphocytes. An increase in CD4(+) CD25(+) forkhead box protein 3 (FoxP3)(+) [regulatory T cell [(Treg)] numbers was also seen. Treg increase correlated with a higher proliferation rate of this regulatory subpopulation when compared with the CD4(+) FoxP3(-) effector counterpart. Basal phosphorylation level of S6 kinase, a major mTOR-dependent molecular target, was substantially maintained in patients treated with everolimus. Moreover, oscillations in serum concentration of everolimus were associated with changes in basal and activation-dependent S6 kinase phosphorylation of CD4(+) and CD8(+) T cells. Indeed, T cell receptor (TCR) triggering was observed to induce significantly higher S6 kinase phosphorylation in the presence of lower everolimus serum concentrations. These results unveil the complex mTOR-dependent immune-metabolic network leading to long-term immune-modulation and might have relevance for novel therapeutic settings in kidney transplants.
authors.affiliation: Dipartimento di Sanità Pubblica, DH di Nefrologia e Trapianto di Rene, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sabbatini
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ruggiero
authors.affiliation: Dottorato di Scienze.|Dipartimento di Scienze, Università della Basilicata, Potenza, Italy.
authors.forename: A T
authors.initials: AT
authors.lastname: Palatucci
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Rubino
authors.affiliation: Dipartimento di Sanità Pubblica, DH di Nefrologia e Trapianto di Rene, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Federico
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università di Napoli 'Federico II', Napoli, Italy.|Dipartimento di Scienze, Università della Basilicata, Potenza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Giovazzino
authors.affiliation: Dipartimento di Sanità Pubblica, DH di Nefrologia e Trapianto di Rene, Università di Napoli 'Federico II', Napoli, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Apicella
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli 'Federico II', Napoli Italy.
authors.forename: M
authors.initials: M
authors.lastname: Santopaolo
authors.affiliation: Dipartimento di Medicina e Chirurgia, Università di Salerno, Salerno, Italy.|Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Matarese
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Galgani
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università di Napoli 'Federico II', Napoli, Italy.|Dipartimento di Scienze, Università della Basilicata, Potenza, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Terrazzano
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D065095:Calcineurin Inhibitors / Q000627:therapeutic use; D049109:Cell Proliferation; D000068338:Everolimus / Q000097:blood / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D019893:Ribosomal Protein S6 Kinases / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D065095:Calcineurin Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma; D000068338:Everolimus; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases
keywords: everolimus; immunosuppression; kidney transplants; mTOR