Interleukin-17–Producing T-Helper Cells as New Potential Player Mediating Graft-Versus-Host Disease in Patients Undergoing Allogeneic Stem-Cell Transplantation

Dander, Erica; Balduzzi, Adriana; Zappa, Greta; Lucchini, Giovanna; Perseghin, Paolo; Andrè, Valentina; Todisco, Elisabetta; Rahal, Daoud; Migliavacca, Maddalena; Longoni, Daniela; Solinas, Graziella; Villa, Antonello; Berti, Emilio; Mina, Pamela Della; Parma, Matteo; Allavena, Paola; Biagi, Ettore; Rovelli, Attilio; Biondi, Andrea; D’Amico, Giovanna

doi:10.1097/tp.0b013e3181bc267e

Cited by 113 publications

(125 citation statements)

References 50 publications

(47 reference statements)

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“…8 Finally, blockade of both Th1 and Th17 differentiation is required to prevent GVHD in mice. 9 In humans, an increased Th17 population in blood was observed in patients with aGVHD, 10 it was also reported that the imbalance between Th17 and regulatory T cells can be correlated with the pathological grade of GVHD. 11 In cutaneous GVHD, Broady et al 12 found an expansion of tissue-localized Th1 and not Th17 cells.…”

Section: Introductionmentioning

confidence: 99%

Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease

et al. 2012

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The contribution of Th17 cells in acute graft-versus-host disease (aGVHD) has been demonstrated in aGVHD mouse models. However, their contribution in human gastrointestinal aGVHD remains unclear. We evaluated Th17 cells in a cohort of 23 patients at diagnosis of aGVHD. In this study, we have shown that the absolute number of Th17 cells using the CCR6 and CD161 markers were significantly higher in the intestinal mucosa of patients with aGVHD compared with intestinal mucosa of patients without aGVHD. Moreover, in keeping with the increase of CCR6 þ and CD161 þ T cells, RORgt the key transcription factor that orchestrates the differentiation of Th17 cells, was significantly increased in the intestinal mucosa of patients with aGVHD compared with intestinal mucosa of patients without aGVHD (P ¼ 0.01). Since plasmacytoid dendritic cells (PDCs) have been reported to drive the differentiation of the Th17 subset, we quantified PDCs in these patients. PDC CD123 þ cells were increased in the intestinal mucosa of patients with aGVHD. Furthermore, the number of CD123 þ PDCs paralleled the histological grade of aGVHD, providing evidence for a role of Th17-mediated responses and a potential new pathophysiological link between PDCs and Th17 in human aGVHD.

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Section: Introductionmentioning

confidence: 99%

Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease

et al. 2012

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“…1,7 The role of T helper (Th)1-induced cytotoxic T lymphocytes as effector cells of aGVHD has been challenged by numerous mouse studies demonstrating an involvement of not only Th1 [7][8][9][10][11][12] but also Th2 8,9,12,13 and Th17 cells. 8,11,14,15 Studies in aGVHD patients investigating either circulating 12,[16][17][18][19][20][21] or skin-localized [17][18][19]22 T-cell subsets have yielded conflicting results. In aGVHD skin, either increased 17,22 or decreased numbers 18,19 of Th17 cells were reported to occur.…”

Section: Introductionmentioning

confidence: 99%

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease

Brüggen

Klein

Greinix³

et al. 2014

Blood

105

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Key Points• Distinct T-cell patterns characterize the acute and chronic forms of cutaneous GVHD.• Increased TSLP expression is an indicator of acute cutaneous GVHD development.Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT) and can present in an acute (aGVHD), a chronic lichenoid (clGVHD), and a chronic sclerotic form (csGVHD). It is unclear whether similar or different pathomechanisms lead to these distinct clinical presentations. To address this issue, we collected lesional skin biopsies from aGVHD (n 5 25), clGVHD (n 5 17), and csGVHD (n 5 7) patients as well as serial nonlesional biopsies from HCT recipients (prior to or post-HCT) (n 5 14) and subjected them to phenotypic and functional analyses. Our results revealed striking differences between aGVHD and clGVHD. In aGVHD, we found a clear predominance of T helper (Th)2 cytokines/chemokines and, surprisingly, of interleukin (IL)-22 messenger RNA as well as an increase of IL-22-producing CD4 1 T cells.Thymic stromal lymphopoietin, a cytokine skewing the immune response toward a Th2 direction, was elevated at day 20 to 30 post-HCT in the skin of patients who later developed aGVHD. In sharp contrast to aGVHD, the immune response occurring in clGVHD showed a mixed Th1/Th17 signature with upregulated Th1/Th17 cytokine/chemokine transcripts and elevated numbers of interferon-g-and IL-17-producing CD8

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“…Patients received from 2 to 5 cell infusions. The median dose of cells infused was 1 Â 10 6 /kg (range ¼ 0.9 --2.9 Â 10 6 /kg). Consistent with our previous study, 3 we confirmed a response rate of around 70% overall, with a complete response in 30% of the patients.…”

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confidence: 99%

“…Moreover, in order to investigate the effect of MSC infusions on lymphocytes circulating in the peripheral blood (PB), we analyzed the ratio between the pro-inflammatory, GvHD-promoting TH1 and TH17 subsets 6,7 and the anti-inflammatory Treg population. 8,9 In CR patients, we observed a change in CD4 þ T-cell subsets after therapy: Tregs increased whereas Th1 and Th17 populations decreased.…”

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confidence: 99%

Mesenchymal stromal cells for the treatment of graft-versus-host disease: understanding the in vivo biological effect through patient immune monitoring

et al. 2012

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Interleukin-17–Producing T-Helper Cells as New Potential Player Mediating Graft-Versus-Host Disease in Patients Undergoing Allogeneic Stem-Cell Transplantation

Abstract: These findings support the hypothesis that TH-17 are involved in the active phases of GVHD and may represent a novel cellular target for developing new strategies for GVHD treatment.

Cited by 113 publications

References 50 publications

Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease

Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease

Mesenchymal stromal cells for the treatment of graft-versus-host disease: understanding the in vivo biological effect through patient immune monitoring

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