title: Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus.
abstract: Tacrolimus and sirolimus are commonly used maintenance immunosuppressants in kidney transplantation. As their effects on immune cells and allograft molecular profiles have not been elucidated, we characterized the effects of tacrolimus to sirolimus conversion on the frequency and function of T cells, and on graft molecular profiles. Samples from renal transplant patients in a randomized trial of 18 patients with late sirolimus conversion and 12 on tacrolimus maintenance were utilized. Peripheral blood was collected at 0, 6, 12, and 24 months post randomization, with T-cell subpopulations analyzed by flow cytometry and T-cell alloreactivity tested by IFN-γ ELISPOT. Graft biopsy samples obtained 24 months post randomization were used for gene expression analysis. Sirolimus conversion led to an increase in CD4(+)25(+++)Foxp3(+) regulatory T cells. While tacrolimus-maintained patients showed a decrease in indirect alloreactivity over time post transplant, sirolimus conversion increased indirect alloreactive T-cell frequencies compared with tacrolimus-maintained patients. No histological differences were found in graft biopsies, but molecular profiles showed activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune response in sirolimus-converted patients. Thus, chronic immune alterations are induced after sirolimus conversion. Despite the molecular profile being favorable to calcineurin inhibitor-based regimen, there was no impact in renal function over 30 months of follow-up.
authors.affiliation: 1] Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA [2] Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gallon
authors.affiliation: 1] Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA [2] Department of Medicine-Nephrology, Thammasart University Hospital, Pathumthani, Thailand.
authors.forename: Opas
authors.initials: O
authors.lastname: Traitanon
authors.affiliation: Department of Pathology, Northwestern University, Chicago, Illinois, USA.
authors.forename: Nedjema
authors.initials: N
authors.lastname: Sustento-Reodica
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Leventhal
authors.affiliation: 1] Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA [2] Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA.
authors.forename: M Javeed
authors.initials: MJ
authors.lastname: Ansari
authors.affiliation: University of Virginia, Department of Surgery, Charlottesville, Virginia, USA.
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Gehrau
authors.affiliation: Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Ariyamuthu
authors.affiliation: 1] Transplantation Research Center, Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Nephrology, Cleveland Clinic Florida, Cleveland, Florida, USA.
authors.forename: Sacha A
authors.initials: SA
authors.lastname: De Serres
authors.affiliation: 1] Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA [2] Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alvarado
authors.affiliation: Advocate Christ Medical Center, Kidney Transplant, Oak Lawn, Illinois, USA.
authors.forename: Darshika
authors.initials: D
authors.lastname: Chhabra
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Mathew
authors.affiliation: 1] Transplantation Research Center, Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Nephrology, Cleveland Clinic Florida, Cleveland, Florida, USA.
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
authors.affiliation: University of Virginia, Department of Surgery, Charlottesville, Virginia, USA.
authors.forename: Valeria
authors.initials: V
authors.lastname: Mas
mesh_terms: D000328:Adult; D064591:Allografts / Q000276:immunology / Q000473:pathology; D017951:Antigen Presentation / Q000235:genetics; D018791:CD4 Lymphocyte Count; D057915:Drug Substitution; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000378:metabolism; D016030:Kidney Transplantation; D008264:Macrophages; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory; D016559:Tacrolimus / Q000627:therapeutic use*; D014181:Transplantation Immunology / Q000187:drug effects* / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents; D018664:Interleukin-12; D007371:Interferon-gamma; D020123:Sirolimus; D016559:Tacrolimus