FOXP3-enriched infiltrates associated with better outcome in renal allografts with inflamed fibrosis.
BACKGROUND
FOXP3-expressing regulatory T cells (Tregs) play a crucial role in maintaining allogeneic transplant tolerance in experimental models. In clinical transplantation, there are few data about their role in chronic inflammation. We hypothesized that Tregs might accumulate within the graft since enrichment of Tregs has been frequently described in chronically inflamed tissues.


METHODS
Sixty-seven biopsies, indicated by a rise in creatinine level, were studied. Thirty-four biopsies showing acute T-cell-mediated rejection and 33 displaying inflamed fibrosis were selected. Tregs frequency was calculated for each infiltrate by counting FOXP3+ and CD3+ cells on two contiguous serial sections.


RESULTS
A total of 121 infiltrates were scored with a mean of 309 CD3+ cells per infiltrate (range: 50-700). Tregs were enriched within allografts exhibiting inflamed fibrosis versus acute cellular rejection (10.6 +/- 6.8% versus 5.5 +/- 2.6%, respectively, P = 0.005). In those with inflammation within scarred areas, the subset of patients with a low FOXP3/CD3 ratio (below the median value) displayed a lower frequency of B-cell-enriched nodular cell clusters (20% versus 86%, P = 0.001) and had a significantly lower graft survival (log-rank, P = 0.02). In multivariate analysis, the low FOXP3/CD3 ratio remained an independent indicator of outcome (P = 0.03). Consistently, the FOXP3+/IL-17+ cell ratio was higher in nodular than in diffuse infiltrates.


CONCLUSIONS
Our results suggest that Tregs may dampen the graft injury in chronic (versus acute) inflammation and stress the importance of devising strategies to enhance Tregs efficiency.
Zuber
Julien
J
Université Paris Descartes, Paris, France. julien.zuber@nck.aphp.fr
Brodin-Sartorius
Albane
A
Lapidus
Naël
N
Patey
Natacha
N
Tosolini
Marie
M
Candon
Sophie
S
Rabant
Marion
M
Snanoudj
Renaud
R
Panterne
Clarisse
C
Thervet
Eric
E
Legendre
Christophe
C
Chatenoud
Lucienne
L
D000328:Adult; D002921:Cicatrix / Q000276:immunology* / Q000473:pathology*; D005260:Female; D005355:Fibrosis / Q000150:complications / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000096:biosynthesis*; D006084:Graft Rejection / Q000150:complications / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000276:immunology; D016030:Kidney Transplantation; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors