Epigenetic quantification of tumor-infiltrating T-lymphocytes

Sehouli, Jalid; Loddenkemper, Christoph; Cornu, Tatjana I.; Schwachula, Tim; Hoffmüller, Ulrich; Grützkau, Andreas; Lohneis, Philipp; Dickhaus, Thorsten; Gröne, Jörn; Kruschewski, M.; Mustea, Alexander; Türbachova, Ivana; Baron, Udo; Olek, Sven

doi:10.4161/epi.6.2.13755

Cited by 79 publications

(86 citation statements)

References 42 publications

(48 reference statements)

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“…Epigenetic immunophenotyping has been recently shown to be as precise as FACS for T-cell quantification. 30 Indeed, this is consistent with previous studies…”

Section: Resultssupporting

confidence: 83%

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus

et al. 2011

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“…Epigenetic immunophenotyping has been recently shown to be as precise as FACS for T-cell quantification. 30 Indeed, this is consistent with previous studies…”

Section: Resultssupporting

confidence: 83%

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus

et al. 2011

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“…Given the importance of IL-2 in driving FOXP3 expression and the modest decrease we observed in FOXP3 expression in Tregs during DAC HYP therapy, we sought to determine whether CD25 blockade effected TSDR methylation status. To perform this analysis, we measured epigenetically committed, stable Tregs using a quantitative PCR assay that enumerates Tregs based on the presence of a demethylated TSDR, termed TSDR + Tregs (25,33). In addition, total cells and CD3 + T cells were simultaneously quantified in the sample using epigenetic analysis of the GAPDH and CD3D/CD3G loci, respectively, and TSDR + Tregs were calculated as a percentage of total PBMCs or as a percentage of total CD3 + T cells.…”

Section: Tregs That Remain In Dac Hyp-treated Patients Maintain Tsdr mentioning

confidence: 99%

“…Treg-specific demethylated region (TSDR) analysis was performed by Epiontis (Berlin, Germany), as described previously (25). The method was further developed and validated for use with cryopreserved PBMCs.…”

Section: Treg-specific Demethylated Region Analysismentioning

confidence: 99%

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Huss

Mehta

Sharma

et al. 2015

The Journal of Immunology

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Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor α subunit (IL-2Rα or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ∼50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a demethylated Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN-γ, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2Rβγ signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.

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“…DNA methylation analysis was performed from genomic DNA after bisulfite conversion and qPCR as previously shown [42]. All epigenetic analyses were performed by Fa.…”

Section: Dna Methylation Analysismentioning

confidence: 99%

Isolation of human antigen‐specific regulatory T cells with high suppressive function

et al. 2014

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Adoptive transfer of regulatory T (Treg) cells could be an alternative to chronic immunosuppression for prevention of allogeneic graft rejection. While polyspecific Treg cells can prevent immune responses under lymphopenic conditions, Ag-specific Treg cells are needed to treat autoimmunity and graft rejection. Yet, reliable markers for Ag-specific Treg cells are missing. We report that latency-associated peptide (LAP) and glycoprotein A repetitions predominant (GARP) can identify human Ag-specific Treg cells. In addition,we show that the depletion of CD154 + cells from LAP + or GARP + Treg cells increases the Treg-cell purity to over 90%, as assessed by epigenetic analysis. These Ag-specific Treg cells can be isolated magnetically and might contribute to the development of GMP-based protocols. In addition, Ag-specific Treg cells are functionally far superior to CD4 + CD25 high or CD4 + CD25 high CD127 low Treg cells in vitro and in preventing strong alloreactions in humanized mice. They could, therefore, have a high therapeutic potential for the control of alloimmune, autoimmune, and allergic immune responses in patients.Keywords: Antigen-specific r CD154 r GARP r LAP r Regulatory T (Treg) cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIn organ transplantation, acute rejection can be prevented by a combination of nonspecific immunosuppressive drugs and immunomodulatory induction therapies, yet chronic rejection and chronic graft dysfunction remain a clinical problem [1]. In addition, chronic nonspecific immunosuppression causes renal dysfunction and predisposes patients to infections and increased Correspondence: Dr. Elmar Jaeckel e-mail: Jaeckel.Elmar@mh-hannover.de risk of malignancies [1]. Innate and adaptive immune responses can be controlled by Treg cells, thereby offering new therapeutic options after organ transplantation [2][3][4][5][6]. CD4 + CD25 high FOXP3 + Treg cells have been shown to be of major importance in allospecific tolerance in animal models and to influence donor-specific immune responses in transplant patients [7][8][9][10]. After allogeneic hematopoietic stem cell transplantation, polyspecific Treg cells can prevent GVH disease without influencing * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2592-2602 Cellular immune response 2593 graft-versus-leukemia responses [11,12]. Therefore, polyspecific CD4 + CD25 high cells are currently being evaluated after stem cell transplantation [13]. However, under nonlymphopenic conditions as seen in patients with autoimmune diseases or in patients after organ transplantation, polyspecific Treg cells have so far been largely ineffective in controlling immune responses [5,14,15] [24], and CD137 (4-1BB) [25] were described as Treg-cell activation markers after polyspecific Treg-cell activation.In this manuscript, we demonstrated for the first time that LAP and GARP can be use...

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Epigenetic quantification of tumor-infiltrating T-lymphocytes

Cited by 79 publications

References 42 publications

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Isolation of human antigen‐specific regulatory T cells with high suppressive function

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