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

Brodin-Sartorius, Albane; Lapidus, Nathanaël; Patey, Natacha; Tosolini, Marie; Candon, Sophie; Rabant, Marion; Snanoudj, Renaud; Panterne, Clarisse; Thervet, Éric; Legendre, Christophe; Chatenoud, Lucienne

doi:10.1093/ndt/gfp435

Cited by 26 publications

(31 citation statements)

References 35 publications

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“…Indeed, IL-10-producing Tregs were detected in the interstitium of rejected grafts and enrichment in IL-10 was observed in the cytokinic microenvironments of the slow progressor grafts. These data suggest that Tregs play an important role in slowing down the chronic rejection process, as previously proposed (9)(10)(11). On the other hand, it is important to note that renal grafts from the two groups displayed similar levels of infiltration by immune effectors.…”

Section: Discussionsupporting

confidence: 82%

“…These works have led to the conclusion that the grafts may be destroyed indifferently by Th1, Th2 (5, 6), or Th17 (7,8) cells, although with variable kinetics and through different pathogenic mechanisms. In contrast, Tregs appeared to exert a protective effect against rejection (9)(10)(11). However, because most of these studies have been conducted in transgenic murine experimental models, the validity of the findings in a clinical chronic rejection setting remains largely elusive.…”

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confidence: 99%

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Intragraft Th17 Infiltrate Promotes Lymphoid Neogenesis and Hastens Clinical Chronic Rejection

Deteix

Attuil-Audenis

Duthey

et al. 2010

The Journal of Immunology

147

124

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To evaluate the influence of intragraft inflammatory infiltrate on the course of chronic rejection, 11 human renal grafts, detransplanted for terminal failure, were analyzed. Samples were divided into two groups according to their graft survival (> or ≤8 y). In both groups, the main cell population infiltrating the graft interstitia was T lymphocytes. The extent of the lymphocytic infiltration and the distribution of naive and memory, CD4+ and CD8+ T cells, were similar in both groups. Although all types of Th polarization profiles can lead to terminal chronic rejection, a correlation between shorter graft survival and the presence of Th17 cells that produce IL-17 and IL-21 was observed. In contrast, grafts infiltrated by regulatory T cells survived significantly longer. The correlation between the expressions of activation-induced cytidine deaminase (the key enzyme of the germinal center reaction) and IL-21 suggests that Th17 could exert their deleterious effect by promoting lymphoid neogenesis, namely, the organization of inflammatory effectors into ectopic germinal centers in which a local humoral immune response is elicited. Further studies will determine whether Th17 infiltration can be used as a prognosis tool and whether theTh17 subset constitutes a therapeutic target for slowing down chronic rejection.

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Intragraft Th17 Infiltrate Promotes Lymphoid Neogenesis and Hastens Clinical Chronic Rejection

Deteix

Attuil-Audenis

Duthey

et al. 2010

The Journal of Immunology

147

124

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“…6,7,35 In accordance with these findings, lower frequencies of Tregs have been correlated with poor graft outcomes. 4,11,34,36 Despite accumulating data from various experimental models, the present clinical results are insufficient to prove that Tregs play a role in the maintenance of tolerance in operationally tolerant recipients. In this article, we report on increased Foxp3 demethylation and a higher frequency of circulating mTregs in the blood of tolerant recipients compared with nontolerant equivalents and healthy controls.…”

Section: Discussionmentioning

confidence: 79%

Central Role of CD45RA− Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance

Braza

Dugast

Panov

et al. 2015

Journal of the American Society of Nephrology

105

102

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“…32 Alternatively, this phenomenon could not indicate alloimmunity, but simply reflect the process of natural stabilization of inflamed sites operated by T regulatory cells, not associated with better graft survival, as suggested by Bunnag et al 12 These authors reported increased FOXP3 expression in late kidney allograft biopsies as compared to early biopsies, which was correlated with inflammation, injury, and repair assessed by pathogenesis-based transcript microarrays.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2013

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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.

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

Abstract: 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.

Cited by 26 publications

References 35 publications

Intragraft Th17 Infiltrate Promotes Lymphoid Neogenesis and Hastens Clinical Chronic Rejection

Intragraft Th17 Infiltrate Promotes Lymphoid Neogenesis and Hastens Clinical Chronic Rejection

Central Role of CD45RA− Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance

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

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