title: End-stage renal failure and regulatory activities of CD4+CD25bright+FoxP3+ T-cells.
abstract: BACKGROUND
  The defensive immune system in patients with end-stage renal failure is impaired at multiple levels. This state of immune incompetence is associated with continuous activation of the immune system. An additional explanation for this state of activation may be the disturbed function of CD4(+)CD25(bright+)FoxP3(+) regulatory T-cells.
  
  
  METHODS
  The phenotype and function of peripheral regulatory T-cells from patients with end-stage renal failure (N = 80) and healthy controls (N = 17) was studied by flow cytometry, RT-PCR and mixed lymphocyte reaction. Patients were on haemodialysis (N = 40), peritoneal dialysis (N = 26) or not treated with dialysis yet (N = 14). The latter group had a glomerular filtration rate of <20 ml/min/ 1.73 m(2).
  
  
  RESULTS
  The basal IL-2 mRNA level was high in patient-PBMC (P = 0.0002 versus healthy controls). The absolute number of CD4(+)CD25(bright+) T-cells was low in patients (P < 0.05 versus healthy controls). Furthermore, proliferation of patient-PBMC upon allogeneic stimulation was impaired (P < 0.0001 versus healthy controls). The regulatory function of CD4(+)CD25(bright+) T-cells was determined in the setting of direct allorecognition. First, the effect of depletion of CD25(bright+) cells from patient-PBMC on proliferation was low. Second, co-culture of CD25(bright+) cells with CD25(neg/dim) cells (1:10 ratio) showed impaired regulatory function (P < 0.001 versus healthy controls), which was especially pronounced in patients on dialysis. The FOXP3 mRNA level was also low upon stimulation (P = 0.0002 versus healthy controls).
  
  
  CONCLUSIONS
  In line with previous studies, we observed an overactivated but functionally compromised immune system in patients with end-stage renal failure. It now appears that in this setting, regulation by CD4(+)CD25(bright+)FoxP3(+) T-cells is also impaired.
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: Thijs K
authors.initials: TK
authors.lastname: Hendrikx
authors.forename: Eveline A F J
authors.initials: EA
authors.lastname: van Gurp
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Mol
authors.forename: Wenda
authors.initials: W
authors.lastname: Schoordijk
authors.forename: Varsha D K D
authors.initials: VD
authors.lastname: Sewgobind
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Ijzermans
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D000328:Adult; D000368:Aged; D015704:CD4 Antigens / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D010530:Peritoneal Dialysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D006435:Renal Dialysis; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508594:IL2 protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger