Review Article

Are We Ready for the Use of Foxp3+ Regulatory T Cells for Immunodiagnosis and Immunotherapy in Kidney Transplantation?

Table 1

Studies supporting the association of regulatory T cells with diagnosis of kidney rejection and graft outcomes prediction.

ReferenceStudy designPatient characteristicsImmunodiagnostic findingsGraft outcomesConclusions/additional comments

Muthukumar et al. [49]Prospective83 total pts (36 pts with graft dysfunction and BPAR)Increased Foxp3 transcripts in urinary cells in pts with BPARBetter kidney function and lower risk of graft failure in pts with BPAR and higher levels of Foxp3 transcriptsDemonstration of potential role of the measurement of Foxp3 transcripts for diagnosis of rejection and outcomes prediction

Wang et al. [50]Prospective10 living-donor transplant pts with BPARIncreased Foxp3 transcripts in peripheral blood associated with BPARMeasurement of Foxp3 transcripts in peripheral blood may aid the immunodiagnosis of rejection in living-donor transplantation/sample size too small to be conclusive, but findings are encouraging

Martin et al. [51]Retrospective11 of 17 pts with acute BPARPatients with Foxp3+ infiltrates had better kidney function and lower rates of graft loss at 1-year posttransplantationTregs infiltration in graft might correlate with favourable graft outcomes/sample size too small to be conclusive and some patients who lost their graft had evidence of humoral rejection

Aquino-Dias et al. [52]Prospective35 pts with DGF (total 48 biopsies: 20 with BPAR and 28 with ATN)Increased Foxp3 transcripts in kidney tissue, peripheral blood and urinary cells correlated with BPAR when compared to ATNMeasurement of Foxp3 transcripts may aid the early identification of rejection for pts with DGF

Grimbert et al. [53]Cross-sectional26 pts with kidney dysfunction (15 pts with borderline rejection and 11 with type IA acute TCMR)Higher ratios for the transcripts of Foxp3/granzyme B were found in pts with borderline rejection in comparision with pts with type IA acute TCMRTregs could play a protective role ameliorating inflammation and preventing the progression to frank rejection

Mansour et al. [54]Retrospective46 pts with borderline rejectionIncreased Foxp3 transcripts in pts with stable creatinine compared to pts who progressed to BPARNo difference found in kidney function at 2 years in both pts with treated BPAR and pts with stable creatinineMeasurement of Foxp3 transcripts may have prognostic value in borderline rejection

Bestard et al. [56]Retrospective37 pts with SCR from 170 protocol biopsiesFewer Tregs were observed in pts on ciclosporinThe presence of Treg infiltrates correlated with better graft function at 2- and 3-years posttransplantationPresence of Tregs infiltration could prevent the progression from SCR to clinical rejection

Bestard et al. [18]Retrospective37 pts with SCRNumber of infiltrating Tregs in pts with SCR correlated with Foxp3 demethylation at the Treg-specific demethylation regionThe presence of Treg infiltrates correlated with better graft function and survival up to 5-year posttransplantationPresence of Tregs infiltration in rejection associates with better graft outcomes/the Banff classification alone is insufficient for immunodiagnosis and prognostication purposes

Xu et al. [57]Retrospective125 pts with protocol biopsies with presence of T cell infiltrates (14 with SCR, 32 with borderline rejection, 79 with no rejection)Higher ratios for the transcripts of Foxp3/granzyme B correlated with lower risk for rejectionHigher ratios for the transcripts of Foxp3/granzyme B predicted better kidney function and graft survival up to 5-year posttransplantationTregs could play a protective role reducing rejection risk and improving graft outcomes/unable to provide conclusions for pts without T cell infiltrates

Zuber et al. [58]Retrospective67 pts (34 with acute TCMR, 33 with chronic TCMR)Higher number and ratio of Tregs over total T cells were observed in patients with chronic rejection than with acute rejectionThe greater the Treg infiltrate in inflamed scarred areas, the better the graft survivalTregs might be protective in chronic rejection

ATN: acute tubular necrosis; BPAR: biopsy proven acute rejection; DGF: delayed graft function; pts: patients; SCR: subclinical rejection; TCMR: T-cell-mediated rejection. Blank area: not assessed.