title: Calcineurin and mTOR inhibitors have opposing effects on regulatory T cells while reducing regulatory B cell populations in kidney transplant recipients.
abstract: BACKGROUND
  Regulatory B (Breg) and T (Treg) cells represent a biomarker for tolerance in transplant patients. Despite the importance of Treg and Breg in transplantation and the suggested crosstalk between both suppressive cell populations, little is known on how they are influenced by long-term immunosuppressive treatment. The aim of the present study was to investigate the effect of different immunosuppressive drugs used in routine clinical practice on Treg and Breg cell numbers.
  
  
  METHODS
  Thirty-six kidney transplant recipients with stable graft function were recruited and classified according to their concomitant therapy: 22 patients received calcineurin inhibitors (CNI) and 14 patients received mammalian target of rapamycin (mTOR) inhibitors. A group of 8 healthy untreated subjects was included as control. Absolute numbers of peripheral blood-derived IL10-producing B cells (CD19(+)IL10(+)), CD19(+)CD24(hi)CD38(hi) transitional B cells and Treg cells (CD4(+)CD25(+)FOXP3(+)) were quantified in all KT patients and controls by flow cytometry.
  
  
  RESULTS
  CD19(+)CD24(hi)CD38(hi) transitional B cells increased over time and seem to be related with long-term therapeutic graft survival irrespective of the treatment regimen. CNI and mTOR inhibitors significantly reduced numbers of Breg cells when compared with healthy individuals, whereas mTOR inhibitors expanded Treg cells in comparison with CNI drugs.
  
  
  CONCLUSIONS
  Bridging the drug-mediated reduction of Breg cell numbers in vivo with the requirements of Breg cells for long-term transplant success remains an as yet unresolved task for therapeutic intervention. Further larger cohort studies that evaluate the effect of different treatment regimen on defined lymphocyte subpopulations are warranted.
authors.affiliation: Infection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: irelatorre@gmail.com.
authors.forename: Irene
authors.initials: I
authors.lastname: Latorre
authors.affiliation: Infection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: a.estevesole@gmail.com.
authors.forename: Ana
authors.initials: A
authors.lastname: Esteve-Sole
authors.affiliation: Department of Nephrology, Hospital del Mar. Institute Hospital del Mar for Medical Research (IMIM), Barcelona, Spain. Electronic address: doloredondop@gmail.com.
authors.forename: Dolores
authors.initials: D
authors.lastname: Redondo
authors.affiliation: Infection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: sandragiest-research@yahoo.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Giest
authors.affiliation: Infection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: jordi.argilaguet@upf.edu.
authors.forename: Jordi
authors.initials: J
authors.lastname: Argilaguet
authors.affiliation: Department of Nephrology, Hospital del Mar. Institute Hospital del Mar for Medical Research (IMIM), Barcelona, Spain. Electronic address: saraalvarez.mo@gmail.com.
authors.forename: Sara
authors.initials: S
authors.lastname: Alvarez
authors.affiliation: Infection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: cristina.peligero@upf.edu.
authors.forename: Cristina
authors.initials: C
authors.lastname: Peligero
authors.affiliation: Infection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: isabellef@web.de.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Forstmann
authors.affiliation: Department of Nephrology, Hospital del Mar. Institute Hospital del Mar for Medical Research (IMIM), Barcelona, Spain. Electronic address: MCrespo@parcdesalutmar.cat.
authors.forename: Marta
authors.initials: M
authors.lastname: Crespo
authors.affiliation: Department of Nephrology, Hospital del Mar. Institute Hospital del Mar for Medical Research (IMIM), Barcelona, Spain. Electronic address: jpascualsantos@parcdesalutmar.cat.
authors.forename: Julio
authors.initials: J
authors.lastname: Pascual
authors.affiliation: Infection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Electronic address: andreas.meyerhans@upf.edu.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyerhans
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D060151:B-Lymphocytes, Regulatory / Q000276:immunology*; D065095:Calcineurin Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D016030:Kidney Transplantation; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D014181:Transplantation Immunology / Q000187:drug effects*
chemical_list: D015703:Antigens, CD; D065095:Calcineurin Inhibitors; C508609:IL10 protein, human; D016753:Interleukin-10; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Immunosuppressive drugs; Regulatory B cells; Regulatory T cells; Transplantation