title: Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury.
abstract: BACKGROUND
  In kidney transplant recipients with alemtuzumab induction maintained on mycophenolate mofetil (MMF) immunosuppression, sirolimus (SRL) promotes significant expansion of circulating CD4+CD25high regulatory T cells (Treg). This might translate into more effective protection against chronic graft injury compared to cyclosporin A (CsA), which, in the same clinical setting, does not affect Treg.
  
  
  METHODS
  To assess this hypothesis, in the extension of a single-center, prospective, randomized, open, blind endpoint study aimed to assess the effect of low-dose SRL or CsA on circulating Treg, we compared the outcomes of renal transplant recipients on SRL (n=11) or CsA (n=10) by per-protocol biopsies and serial measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), and 24-hour proteinuria over 30 months posttransplant.
  
  
  RESULTS
  Despite 4-fold higher CD4+CD25high Treg counts (22.1+/-12.2% vs. 5.7+/-4.2% of CD3+CD4+ T cells), SRL-treated patients, compared to CsA-treated patients, had a significantly higher tubular C4d staining score (1.1+/-0.6 vs. 0.2+/-0.3, P<0.01), with nonsignificant trends to higher chronic allograft damage index score (5.6+/-2.4 vs. 3.7+/-3.3), faster GFR (-2.92+/-0.33 vs. -0.28+/-0.44 ml/min/1.73 m2 per year), and RPF (-10.80+/-5.45 vs. -1.86+/-3.09 ml/min/1.73 m2 per year) decline, and more clinical proteinuria (n=6 vs. 4). There was no significant correlation between Treg counts and any considered outcome variable in the study group as a whole and within each cohort.
  
  
  CONCLUSIONS
  These data suggest that, despite enhanced Treg expression, low-dose SRL combined to alemtuzumab induction and MMF-based steroid-free maintenance therapy, does not appreciably protect renal transplant recipients from chronic allograft injury and dysfunction.
authors.affiliation: Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo, Mario Negri Institute for Pharmacological Research, Transplant Research Center Chiara Cucchi De Alessandri e Gilberto Crespi, Bergamo, Italy. ruggenenti@marionegri.it
authors.forename: Piero
authors.initials: P
authors.lastname: Ruggenenti
authors.forename: Norberto
authors.initials: N
authors.lastname: Perico
authors.forename: Eliana
authors.initials: E
authors.lastname: Gotti
authors.forename: Paolo
authors.initials: P
authors.lastname: Cravedi
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.forename: Elena
authors.initials: E
authors.lastname: Gagliardini
authors.forename: Mauro
authors.initials: M
authors.lastname: Abbate
authors.forename: Flavio
authors.initials: F
authors.lastname: Gaspari
authors.forename: Dario
authors.initials: D
authors.lastname: Cattaneo
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Federica
authors.initials: F
authors.lastname: Casiraghi
authors.forename: Marta
authors.initials: M
authors.lastname: Todeschini
authors.forename: Daniela
authors.initials: D
authors.lastname: Cugini
authors.forename: Sara
authors.initials: S
authors.lastname: Conti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use*; D005260:Female; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D020123:Sirolimus / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus