Human Regulatory T Cells of G-CSF Mobilized Allogeneic Stem Cell Donors Qualify for Clinical Application

Ukena, Sya N.; Velaga, Sarvari; Goudeva, Lilia; Ivanyi, Philipp; Olek, Sven; Falk, Christine S.; Ganser, Arnold; Franzke, Anke

doi:10.1371/journal.pone.0051644

Cited by 24 publications

(23 citation statements)

References 35 publications

(33 reference statements)

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“…This is consistent with previous reports indicating that G-CSF-induces an increase in the number of IL-10-positive cells, as well as other reports in which the number of CD4 + Treg and some of their regulatory molecules also increased [32, 33]. It is worth noting that this increase was not induced in CD8 + TGF β + cells, a cytokine being widely recognized for its regulatory role [34].…”

Section: Resultssupporting

confidence: 92%

Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease

Gutiérrez‐Hoya

López‐Santiago

Vela‐Ojeda

et al. 2017

Journal of Immunology Research

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CD8+ T cells that secrete proinflammatory cytokines play a central role in exacerbation of inflammation; however, a new subpopulation of CD8 regulatory T cells has recently been characterized. This study analyzes the prominent role of these different subpopulations in the development of graft-versus-host disease (GVHD). Samples from 8 healthy donors mobilized with Filgrastim® (G-CSF) and 18 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated by flow cytometry. Mobilization induced an increase in Tc1 (p < 0.01), Th1 (p < 0.001), Tc17 (p < 0.05), and CD8+IL-10+ cells (p < 0.05), showing that G-CSF induces both pro- and anti-inflammatory profiles. Donor-patient correlation revealed a trend (p = 0.06) toward the development of GVHD in patients who receive a high percentage of Tc1 cells. Patients with acute GVHD (aGVHD), either active or controlled, and patients without GVHD were evaluated; patients with active aGVHD had a higher percentage of Tc1 (p < 0.01) and Tc17 (p < 0.05) cells, as opposed to patients without GVHD in whom a higher percentage of CD8 Treg cells (p < 0.01) was found. These findings indicate that the increase in Tc1 and Tc17 cells is associated with GVHD development, while regulatory CD8 T cells might have a protective role in this disease. These tests can be used to monitor and control GVHD.

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Section: Resultssupporting

confidence: 92%

Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease

Gutiérrez‐Hoya

López‐Santiago

Vela‐Ojeda

et al. 2017

Journal of Immunology Research

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“…These findings are largely applicable to mobilized blood stem cell grafts, because granulocyte-colony stimulating factor, which is used to mobilize stem cells, barely favors Treg over Tconv mobilization. 42 Our data are consistent with the hypothesis that the predominance of alloreactive Tconv over Treg in the graft drives the immune response to cause GVHD and that the expansion of mHA-specific Tregs by an average of 24-fold in a blood cell graft may be adequate to prevent GVHD. Others computed that much greater expansion of polyspecific Tregs is required for effective immunotherapy.…”

Section: Discussionsupporting

confidence: 89%

Human regulatory T cells against minor histocompatibility antigens: ex vivo expansion for prevention of graft-versus-host disease

Veerapathran¹,

Pidala²,

Beato³

et al. 2013

Blood

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• This is the first report about the detection of human Tregs specific for minor histocompatibility antigens.• We detected, quantified, and cloned mHA-specific Tregs and expanded these potent Tregs in sufficient numbers for use in human transplantation.Alloreactive donor T cells against host minor histocompatibility antigens (mHAs) cause graft-versus-host disease (GVHD) after marrow transplantation from HLAidentical siblings. We sought to identify and expand regulatory CD4 T cells (Tregs) specific for human mHAs in numbers and potency adequate for clinical testing. Purified Tregs from normal donors were stimulated by dendritic cells (DCs) from their HLA-matched siblings in the presence of interleukin 2, interleukin 15, and rapamycin. Male-specific Treg clones against H-Y antigens DBY, UTY, or DFFRY-2 suppressed conventional CD4 T cell (Tconv) response to the specific antigen. In the blood of 16 donors, we found a 24-fold (range, 8-fold to 39-fold) excess Tconvs over Tregs reactive against sibling mHAs. We expanded mHA-specific Tregs from 4 blood samples and 4 leukaphereses by 155-to 405-fold. Cultured Tregs produced allospecific suppression, maintained demethylation of the Treg-specific Foxp3 gene promoter, Foxp3 expression, and transforming growth factor b production. The rare CD4 T conv and CD8 T cells in the end product were anergic. This is the first report of detection and expansion of potent mHA-specific Tregs from HLA-matched siblings in sufficient numbers for application in human transplant trials. (Blood. 2013;122(13):2251-2261

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“…The use of granulocyte-colony-stimulating-factor (G-CSF) may also be considered to increase Treg mobilization into the peripheral blood for potential extraction during leukapheresis [75]. Under steady state, human bone marrow contains a large fraction of CD4+CD25+Foxp3+ T cells with regulatory function [76].…”

Section: Drugs That Potentiate Tregmentioning

confidence: 99%

“…Under steady state, human bone marrow contains a large fraction of CD4+CD25+Foxp3+ T cells with regulatory function [76]. Recent data suggests that donor Treg after G-CSF stimulated stem cell mobilization retain their potent suppressive and stable phenotype, and, thus, the adoptive transfer of donor Treg after G-CSF stimulation appears to be feasible and safe [75]. The isolation of donor Treg from the stem cell graft will simplify their global clinical application.…”

Section: Drugs That Potentiate Tregmentioning

confidence: 99%

Regulatory T Cells in Allogeneic Stem Cell Transplantation

Michael

Shimoni

Nagler

2013

Clinical and Developmental Immunology

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Growing evidence suggests that cellular adoptive immunotherapy is becoming an attractive though challenging approach in regulating tumor immunity and alloresponses in clinical transplantation. Naturally arising CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a key component in this regard. Over the last decade, a large body of evidence from preclinical models has demonstrated their crucial role in auto- and tumor immunity and has opened the door to their “first-in-man” clinical application. Initial studies in clinical allogeneic stem cell transplantation are very encouraging and may pave the way for other applications. Further improvements in Treg ex vivo or in vivo expansion technologies will simplify their global clinical application. In this review, we discuss the current knowledge of Treg biology and their potential for cell-based immunotherapy in allogeneic stem cell transplantation.

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Human Regulatory T Cells of G-CSF Mobilized Allogeneic Stem Cell Donors Qualify for Clinical Application

Cited by 24 publications

References 35 publications

Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease

Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease

Human regulatory T cells against minor histocompatibility antigens: ex vivo expansion for prevention of graft-versus-host disease

Regulatory T Cells in Allogeneic Stem Cell Transplantation

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