Analysis of FOXP3 Gene and Protein Expressions in Renal Allograft Biopsies and Their Association with Graft Outcomes

Abstract

Background: The transcription factor FOXP3 is increased in acute renal rejection, but its influence on graft outcomes is unclear. This study correlated FOXP3 with dendritic cells and graft outcomes. Methods: We assessed 96 kidney transplants undergoing allograft biopsy for cause. FOXP3 mRNA was analyzed by real-time polymerase chain reaction (PCR) and FOXP3 protein and DCsCD83 þ by immunohistochemistry. Graft function and survival were assessed at 5 years post-transplantation, as well as by independent predictors of graft loss. Results: Intragraft FOXP3 gene and protein expression were significantly correlated (r ¼ 0.541, p < 0.001). Both FOXP3 mRNA and protein were increased in patients with acute rejection (AR). High expression of FOXP3 mRNA or protein in biopsies did not correlate with clinical variables, but there was a trend to higher positive variation in the glomerular filtration rate (GFR) from biopsy to last follow-up. Patients with FOXP3-mRNA high had more DCsCD83 þ in biopsy, but these cells did not associate with AR. Five-year graft survival was not influenced by either FOXP3 mRNA or protein expressions. Conclusions: FOXP3 mRNA and protein had a good correlation in archival renal graft tissue. Increased FOXP3 expression was found in AR and FOXP3 associated with high numbers of DCs. However, both FOXP3 mRNA and protein was not associated with better allograft outcomes.

Thymus-Derived Regulatory T Cells Infiltrate the Cardiac Allograft Before Rejection

“…23,37,38 Adoptive transfer experiments have demonstrated the immunosuppressive capacities of intragraft FOXP3+ T cells 39 ; nevertheless, FOXP3 expression has also been associated with rejection, 26,40 and we previously reported the highest FOXP3 mRNA expression in the rejection cardiac biopsies. 25 Most likely, these conflicting data are explained by the fact that FOXP3 is not exclusively expressed by a single cell type, but is expressed by nTreg, iTreg, and also activated T cells.…”

Regulatory T cells in kidney disease and transplantation

“…180,200 However, FOXP3 þ RNA in urine accompanies clinical kidney allograft rejection rather than graft acceptance in transplant patients, and this is consistent with other renal biopsy studies that show FOXP3 þ measured as protein or RNA was not associated with better renal allograft function. 201,202 Thus, although FOXP3 as a marker of Tregs is found to be increased in rejecting kidneys, this may reflect either a protective response to infiltrating effector cells or the expression of FOXP3 in human effector T cells after activation.…”

Contemporary Strategies and Barriers to Transplantation Tolerance

“… 47 Correlation studies in human kidney transplantation have shown that increased numbers of intragraft FOXP3 + Treg cells are associated with favorable graft outcomes in stable patients under immunosuppressive therapy, 48 though these results have been disputed by other groups. 46 , 49 , 50 Application of Treg cell–based therapies in humans has been an attractive field of research, because T cells can distinguish minute differences between antigens, deliver local effects, and may avoid the loss of protective immunity towards pathogens and tumor antigens seen with most current immunosuppressive therapies due to their lack of specificity. Human Treg cells can also be identified, isolated, and expanded in culture to achieve appropriate doses.…”