MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GVHD

Stickel, Natalie; Prinz, Gabriele; Pfeifer, Dietmar; Hasselblatt, Peter; Schmitt‐Graeff, Annette; Follo, Marie; Thimme, Robert; Finke, Jürgen; Duyster, Justus; Salzer, Ulrich; Zeiser, Robert

doi:10.1182/blood-2014-04-569046

Cited by 92 publications

(95 citation statements)

References 38 publications

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“…Interleukin (IL)-6 plays a central role in GVHD and has recently been shown to be a targetable factor. 25 We observed significantly reduced IL-6 levels in the serum of mice that received Cav-1 2/2 T cells compared with WT T cells ( Figure 2C). …”

Section: Lack Of Cav-1 Expression Of the Donor T Cells Decreases Gvhdmentioning

confidence: 79%

Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells

Schönle

Hartl

Mentzel

et al. 2016

Blood

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Section: Lack Of Cav-1 Expression Of the Donor T Cells Decreases Gvhdmentioning

confidence: 79%

Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells

Schönle

Hartl

Mentzel

et al. 2016

Blood

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“…25,41 However, few expanded human tTregs expressed IFN-g under our conditions, and expression was not affected by miR146b-5p antagomir treatment (supplemental Figure 2). Because control CD4 T cells also expressed miR-146b-5p, albeit at low levels, it seemed possible that downmodulation of this miRNA would induce Foxp3 expression and suppressive function.…”

Section: Resultsmentioning

confidence: 99%

miR-146b antagomir–treated human Tregs acquire increased GVHD inhibitory potency

Hippen

Lemire

et al. 2016

Blood

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“…Overexpression of miR-155 in donor T cells leads to increased GvHD mortality, whereas miR-155 deficiency prevents aGvHD (4). Furthermore, increased miR-146a expression in donor T cells prevents from GvHD development by targeting TNFR-associated factor 6, leading to reduced TNF transcription (5). It has also been shown that blocking the miR17-92 cluster alleviates aGvHD while preserving the graftversus-leukemia (GvL) effect (6).…”

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confidence: 99%

miR-181a Expression in Donor T Cells Modulates Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation

Lee

Wohlan

Dallmann

et al. 2016

The Journal of Immunology

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Because miR-181a has been described to alter T cell activation, we hypothesized that manipulation of miR-181a expression in donor T cells may alter acute graft-versus-host disease (aGvHD) after allogeneic bone marrow transplantation (BMT). We therefore analyzed the impact of enhanced and reduced miR-181a expression in donor T cells on aGvHD induction by lentiviral gene transfer into primary T cells and using miR-181a/b-1 2/2 T cells, respectively. BMT-recipient mice receiving donor T cells with enhanced miR-181a expression showed no signs of aGvHD and survived for the time of follow-up, whereas T cells lacking miR-181a/b-1 accelerated aGvHD. In line with these data, analysis of donor T cells in blood, secondary lymphoid organs, and target organs of aGvHD after BMT showed significantly reduced numbers of miR-181a-transduced T cells, as compared with controls. In addition, expansion of activated T cells with enhanced miR-181a expression was reduced in vitro and in vivo. We further show that anti-apoptotic BCL-2 protein expression is reduced in murine and human T cells upon overexpression of miR-181a, suggesting that regulation of BCL-2-expression by miR-181a may contribute to altered alloreactivity of T cells in aGvHD. These data indicate that proteins regulated by miR-181a may be therapeutic targets for aGvHD prevention. The Journal of Immunology, 2016, 196: 3927-3934.A llogeneic stem cell or bone marrow (BM) transplantation (BMT) is the most effective and often unique curative therapy for a variety of high-risk hematological malignancies, BM failure syndromes, and congenital immune deficiencies. However, graft-versus-host disease (GvHD) remains the most frequent severe complication in BMT, contributing largely to nonrelapse mortality. Acute GvHD (aGvHD) is initiated by an aggressive immune response of donor-derived alloreactive T cells directed against host tissues. After allopriming, donor T cells migrate to typical GvHD target organs such as skin, liver, and/or gut, inducing a strong immune response, which ultimately leads to organ damage and/or failure (1). Accordingly, aGvHD prevention and treatment are performed with immunosuppressive drugs such as corticosteroids, calcineurin inhibitors, and different Abs, among others. However, steroid refractory intestinal aGvHD still has a mortality rate of close to 100%. Therefore, new therapeutic strategies are urgently needed.MicroRNAs (miRNA) are small noncoding RNAs involved in posttranscriptional regulation of gene expression (2, 3). Despite many efforts, however, the precise physiological function of individual miRNAs and their pathophysiological contribution to different disease states still remain elusive. In aGvHD, a role for miRNAs in allogeneic donor T cells has recently been described. Overexpression of miR-155 in donor T cells leads to increased GvHD mortality, whereas miR-155 deficiency prevents aGvHD (4). Furthermore, increased miR-146a expression in donor T cells prevents from GvHD development by targeting TNFR-associated factor 6, leading to reduced T...

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MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GVHD

Abstract: Key Points This study deciphers the regulatory role of miR-146a during GVHD in mice. In humans, the minor genotype of the SNP rs2910164, which reduces expression of miR-146a, was associated with higher GVHD severity.

Cited by 92 publications

References 38 publications

Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells

Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells

miR-146b antagomir–treated human Tregs acquire increased GVHD inhibitory potency

miR-181a Expression in Donor T Cells Modulates Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation

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