title: Conversion to sirolimus in kidney transplant recipients with squamous cell cancer and changes in immune phenotype.
abstract: BACKGROUND
  Conversion to sirolimus from calcineurin inhibitor- (CNI), azathioprine- (AZA) and mycophenolate-based regimens reduces the risk of development of squamous cell carcinoma of the skin (SCC) in kidney transplant recipients (KTRs). Sirolimus conversion may also be protective by permitting beneficial changes in immune phenotype. It is not known how sirolimus will affect immune phenotype in KTRs with SCC.
  
  
  METHODS
  Thirty-two KTRs with SCC were enrolled into this single-blinded randomized study and 13 KTRs randomized to sirolimus (4-10 ng/mL) and prednisolone 5 mg/day.
  
  
  RESULTS
  Six-month post conversion to sirolimus FOXP3(+) CD127(low)CD25(high)CD69(-), the number of T cells (putative Treg) increased significantly (P = 0.008). Natural killer (NK) and CD56(bright) NK cells also increased significantly (P = 0.039 and 0.02). T-cell number only significantly increased in those KTRs where CNI was ceased as part of the conversion to mammalian target of rapamycin inhibitors (mTORi's) (P = 0.031) implying CNI cessation rather than mTORi initiation induced an increase in T-cell number. Increases in the NK cell number was only significant in those KTRs where AZA was ceased (P = 0.040), implying AZA cessation rather than mTORi initiation caused the NK cell number to increase. At 6 months, sirolimus conversion reduces new SCC/year, rate ratio 0.49 (95%CI: 0.15-1.63), P = 0.276. On therapy analysis and intention-to-treat analysis over 24 months, the rate ratios were 0.84 and 0.87, respectively, and did not reach significance.
  
  
  CONCLUSIONS
  Conversion to mTORi from CNI may reveal a pre-existing high Treg phenotype by unmasking CNI inhibition of FOXP3 expression. Cessation of AZA leads to increased NK cell number. High FOXP3(+) T-cell number on conversion to mTORi may predict those KTRs who continue to accrue SCC.
authors.affiliation: Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. robert.carroll@health.sa.gov.au
authors.forename: Robert P
authors.initials: RP
authors.lastname: Carroll
authors.forename: Joanna
authors.initials: J
authors.lastname: Hester
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wood
authors.forename: Paul N
authors.initials: PN
authors.lastname: Harden
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000627:therapeutic use; D019002:CD56 Antigen / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002294:Carcinoma, Squamous Cell / Q000150:complications* / Q000453:epidemiology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012307:Risk Factors; D016037:Single-Blind Method; D020123:Sirolimus / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000150:complications* / Q000453:epidemiology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014180:Transplantation
chemical_list: D019002:CD56 Antigen; D065095:Calcineurin Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D058570:TOR Serine-Threonine Kinases; D001379:Azathioprine; D020123:Sirolimus