Intragraft FOXP3 Protein or mRNA During Acute Renal Allograft Rejection Correlates With Inflammation, Fibrosis, and Poor Renal Outcome

Yapici, Ünsal; Bemelman, Fréderike J.; Scheepstra, Cornelis G.; Roelofs, Joris J. T. H.; Claessen, Nike; Loos, Chris van der; Pant, Karlijn van Donselaar-van der; Bouts, Antonia H.; Idu, Mirza M.; Rowshani, Ajda T.; Berge, Ineke J. M. ten; Florquin, Sandrine

doi:10.1097/tp.0b013e3181a24a4b

Cited by 24 publications

(24 citation statements)

References 25 publications

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“…In two recent studies comparing celiac sufferers with active or treated disease, levels of CD4+CD25+Foxp3+ cells in the blood were higher during active disease [8], [9], however this is the first time this effect has been shown during a controlled, short-term gluten challenge. These results, and those from other studies of Tregs in immunopathology [34], [35] and surgical inflammation [36], indicate that CD4+Foxp3+ cells often accumulate during inflammation, however they may not be functionally suppressive [36]. The suppression of effector T cells by regulatory T cells may be rendered unsuccessful due to upregulation of the negative regulator of TGF-β signalling Smad-7 [37].…”

Section: Discussionmentioning

confidence: 63%

Suppression of Inflammatory Immune Responses in Celiac Disease by Experimental Hookworm Infection

et al. 2011

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We present immunological data from two clinical trials where the effect of experimental human hookworm (Necator americanus) infection on the pathology of celiac disease was evaluated. We found that basal production of Interferon- (IFN-)γ and Interleukin- (IL-)17A from duodenal biopsy culture was suppressed in hookworm-infected participants compared to uninfected controls. Increased levels of CD4+CD25+Foxp3+ cells in the circulation and mucosa are associated with active celiac disease. We show that this accumulation also occurs during a short-term (1 week) oral gluten challenge, and that hookworm infection suppressed the increase of circulating CD4+CD25+Foxp3+ cells during this challenge period. When duodenal biopsies from hookworm-infected participants were restimulated with the immunodominant gliadin peptide QE65, robust production of IL-2, IFN-γ and IL-17A was detected, even prior to gluten challenge while participants were strictly adhering to a gluten-free diet. Intriguingly, IL-5 was produced only after hookworm infection in response to QE65. Thus we hypothesise that hookworm-induced TH2 and IL-10 cross-regulation of the TH1/TH17 inflammatory response may be responsible for the suppression of these responses during experimental hookworm infection.

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Section: Discussionmentioning

confidence: 63%

Suppression of Inflammatory Immune Responses in Celiac Disease by Experimental Hookworm Infection

et al. 2011

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“…In contrast, on human graft biopsies Foxp3 þ cells was detected in biopsies with acute cellular rejection type I and II and the degree of Foxp3 þ infiltrates was associated with worse outcome [28]. Recently, Yapici et al [29 ] demonstrated that presence of Foxp3 þ T cells in infiltrates during acute cellular rejection does not correlate with a response to antirejection therapy but rather predicts renal fibrosis. Thus, protocol biopsies can be very informative revealing new mechanisms and cellular players of graft rejection as well as predicting long-term graft function.…”

Section: The Benefit Of Studying Protocol Biopsiesmentioning

confidence: 89%

State of the art on the research for biomarkers allowing individual, tailor-made minimization of immunosuppression

Sawitzki

Reinke

Pascher

et al. 2010

Current Opinion in Organ Transplantation

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With the recent findings we have gained a better understanding of operational tolerant patients and have identified biomarkers and assays which will be very helpful when guiding partial or complete immunosuppressive minimization. For the future, collaborative efforts are needed to design and perform prospective multicenter trials to validate the identified biomarkers across different laboratories and laboratory platforms.

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“…Indeed, besides AV, we also observed several signs of acute rejection in these specimens. It has been shown that infiltration with GrB + [25] and FOXP3 + [26] cells is associated with episodes of acute rejection. Therefore, it is likely that the presence of a part of these cells we observed in the allografts were the result of such a response.…”

Section: Discussionmentioning

confidence: 99%

Spatial Differences in the Presence of FOXP3+ and GranzymeB+ T Cells between the Intra- and Extravascular Compartments in Renal Allograft Vasculopathy

et al. 2011

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BackgroundAllograft vasculopathy (AV) and native atherosclerosis (NA) share the presence of a T-cell mediated inflammatory response, but differ in overall plaque morphology and growth rate. We studied the distribution and frequency of regulatory- and cytotoxic T cells in the arterial intima lesions in both conditions.Methodology/Principal FindingsThe study is based on vessels of 15 explanted human renal allografts with AV and 10 carotid artery plaques obtained at surgery. Distribution and frequency of cytotoxic- and regulatory T cells, as identified by the expression of Granzyme B (GrB) and FOXP3 was established in NA and AV. Furthermore, we compared the distribution of these cells in AV with the perivascular, interstitial renal tissue using immunohistochemistry. The total number of T cells was much higher in AV than in NA lesions (711±135 and 37±8 CD3/mm2 respectively, p<0.005, mean, ± SEM). Total numbers of FOXP3+ regulatory cells were also significantly increased in AV (36±10 and 0.9±0.3 FOXP3+/mm2 p<0.05), but relative numbers, expressed as a percentage of the total number of CD3+ T cells ((FOXP3+/CD3+) ×100), were not significantly different (4.6%±0.9 and 2.7%±0.6). GrB+ cells were rare in NA, but significantly increased numbers of GrB+ cells were found in AV lesions (85±24 and 0.2±0.1 GrB+/mm2, p<0.05). Perivascular tissues in the allografts showed a higher relative frequency of FOXP3+ cells than adjacent intimal lesions (14.0%±2.7 and 4.6%±0.9, respectively, p<0.05), but a lower frequency of GrB+ cytotoxic T cells (16.1%±2.7 and 22.6%±3.6, p<0.05).ConclusionsSimilar to NA, AV is characterized by a low frequency of intimal FOXP3+ regulatory T cells. Moreover, significant spatial differences exist in the distribution of functional T cell subsets between the intra- and extravascular micro-environments of the graft.

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Intragraft FOXP3 Protein or mRNA During Acute Renal Allograft Rejection Correlates With Inflammation, Fibrosis, and Poor Renal Outcome

Abstract: In conclusion, intragraft FOXP3 at both cellular and molecular levels parallels T-cell infiltration during acute rejection. FOXP3 does not predict response to antirejection therapy. FOXP3 correlates with renal fibrosis, TGF-beta, and poor late renal outcome.

Cited by 24 publications

References 25 publications

Suppression of Inflammatory Immune Responses in Celiac Disease by Experimental Hookworm Infection

Suppression of Inflammatory Immune Responses in Celiac Disease by Experimental Hookworm Infection

State of the art on the research for biomarkers allowing individual, tailor-made minimization of immunosuppression

Spatial Differences in the Presence of FOXP3+ and GranzymeB+ T Cells between the Intra- and Extravascular Compartments in Renal Allograft Vasculopathy

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