title: Application of Operational Tolerance Signatures Are Limited by Variability and Type of Immunosuppression in Renal Transplant Recipients: A Cross-Sectional Study.
abstract: BACKGROUND
  Renal transplant recipients (RTR) frequently develop complications relating to chronic immunosuppression. Identifying RTR who could safely reduce immunosuppression is therefore highly desirable. We hypothesized that "signatures" described in RTR who have stopped immunosuppression but maintained stable graft function ("operational tolerance") may enable identification of immunosuppressed RTR who are candidates for immunosuppression minimization. However, the effect of immunosuppression itself on these signatures and circulating B-cell populations is currently unknown.
  
  
  METHODS
  We undertook a cross-sectional study of 117 RTR to assess the effect of immunosuppression upon circulating B cell populations, humoral alloresponse and 2 previously published "signatures" of operational tolerance.
  
  
  RESULTS
  Immunosuppression associated with alterations in both published "signatures." Azathioprine associated with a decrease in transitional and naive B-cell numbers and calcineurin inhibition associated with an increase in the number of circulating plasmablasts. However, only azathioprine use associated with the presence of donor-specific anti-HLA IgG antibodies. Calcineurin inhibition associated with an increase in total serum IgM but not IgG. Data were corrected for age, time since last transplant, and other immunosuppression.
  
  
  CONCLUSIONS
  Current signatures of operational tolerance may be significantly affected by immunosuppressive regimen, which may hinder use in their current form in clinical practice. Calcineurin inhibition may prevent the development of long-lasting humoral alloresponses, whereas azathioprine therapy may be associated with donor specific antibody development.
authors.affiliation: Oxford Kidney Unit, Churchill Hospital, Oxford, United Kingdom.; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bottomley
authors.affiliation: Transplant Immunology and Immunogenetics, Oxford Transplant Centre, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Mian
authors.initials: M
authors.lastname: Chen
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.; Transplant Immunology and Immunogenetics, Oxford Transplant Centre, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Sue
authors.initials: S
authors.lastname: Fuggle
authors.affiliation: Oxford Kidney Unit, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Harden
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wood