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NDT Advance Access published online on September 3, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp435
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© The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


FOXP3-enriched infiltrates associated with better outcome in renal allografts with inflamed fibrosis

Julien Zuber1,2,3{dagger}, Albane Brodin-Sartorius2,3{dagger}, Naël Lapidus4, Natacha Patey5, Marie Tosolini6, Sophie Candon1,2, Marion Rabant1,3, Renaud Snanoudj3, Clarisse Panterne2, Eric Thervet1,3, Christophe Legendre1,2,3 and Lucienne Chatenoud1,2

1 Université Paris Descartes 2 INSERM, Unité U580, Hopital Necker 3 Service de Transplantation Rénale, Hopital Necker 4 INSERM, Unité UMR-S 707 5 Service d’Anatomopathologie, Hopital Necker 6 INSERM, Unité U 255, Institut des Cordeliers, Paris 75006, France

Correspondence and offprint requests to: J. Zuber; E-mail: julien.zuber{at}nck.aphp.fr



  Abstract

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.

Keywords: FOXP3; nodular infiltrates; regulatory T cell; inflamed fibrosis

{dagger} These authors have equally contributed to the work.

Received for publication: 3. 3.09
Accepted in revised form: 4. 8.09


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