CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma following allogeneic stem cell transplantation

Atanackovic, Djordje; Cao, Yanran; Luetkens, Tim; Panse, Jens; Faltz, Christiane; Arfsten, Julia; Bartels, Katrin; Wolschke, Christine; Eiermann, Thomas; Zander, Axel R.; Fehse, Boris; Bokemeyer, Carsten; Kröger, Nicolaus

doi:10.3324/haematol.11897

Cited by 57 publications

(52 citation statements)

References 43 publications

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“…The finding that MM cells are able to induce the generation of Tregs in vitro further corroborates these results [61]. Furthermore, Tregs have been shown to expand and accumulate in the bone marrow of MM patients after allogeneic stem cell transplantation, and Tregs found in these patients are endowed with a strong inhibitory function, potentially inhibiting anti-myeloma immune control after transplantation [62].…”

Section: Regulatory/suppressive Cellssupporting

confidence: 72%

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Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

Binsfeld

Fostier

Muller

et al. 2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The majority of multiple myeloma patients relapse with the current treatment strategies, raising the need for alternative therapeutic approaches. Cellular immunotherapy is a rapidly evolving field and currently being translated into clinical trials with encouraging results in several cancer types, including multiple myeloma. Murine multiple myeloma models are of critical importance for the development and refinement of cellular immunotherapy. In this review, we summarize the immune cell changes that occur in multiple myeloma patients and we discuss the cell-based immunotherapies that have been tested in multiple myeloma, with a focus on murine models.

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Section: Regulatory/suppressive Cellssupporting

confidence: 72%

“…Highly suppressive Tregs expand and accumulate in the bone marrow after allo-SCT [62], and these cells might be able to convert into myeloma-promoting Th17 cells [25,85]. Murine studies suggest that combining allo-SCT with Id-or DC vaccination provides a possible solution to these issues [81,82].…”

Section: Discussionmentioning

confidence: 99%

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

Binsfeld

Fostier

Muller

et al. 2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…They suggested that Tregs might contribute to the prevention of graft versus host disease via their immunosuppressive effect [18]. Similarly, high Treg populations were noted in the APBSCT (+) patients post surgery in the present study, suggesting that Tregs may play a role in stimulation of the immune system after APBSCT.…”

Section: Erçetin Et Al T Regulatory Cells In Multiple Myelomasupporting

confidence: 53%

“…As such, immunosuppressive CD4+CD25+FOXP3+ Tregs, PD-1, and CD200-a novel prognostic factor in MM-were selected as the subjects of the present study. CD4+CD25+FOXP3+ Tregs have a high level of expression in patients that undergo allogeneic bone marrow transplantation [18]. CD200 is also considered a novel prognostic factor in MM, with high expression [14].…”

Section: Introductionmentioning

confidence: 99%

The correlation between T regulatory cells and autologous peripheral blood stem cell transplantation in multiple myeloma

Ercetin

Aktaş²,

Pişkin³

et al. 2011

Turk J Hematol

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Objective: Multiple myeloma (MM) is characterized by malignant proliferation of plasmocytes and their precursors. T regulatory cells (Tregs) have a role in immunosuppression and control of autoimmunity, and are currently an important topic in the study of immune response to tumor cells. The correlation between Tregs and autologous peripheral blood stem cell transplantation (APBSCT) in MM has not been studied. The aim of this study was to compare CD4+CD25+FOXP3+ Treg, CD200, and PD-1 levels in MM patients that did and did not undergo APBSCT. Materials and Methods: Peripheral blood samples were collected from 28 MM patients ranging in age from 41 to 78 years for analysis of CD4CD25+ FOXP3+ Tregs, PD-1 (CD279), and CD200. Peripheral blood mononuclear cells were isolated via density gradient centrifugation. Four-color flow cytometry was performed. Using a sequential gating strategy, Tregs were identified as CD4+CD25+FOXP3+ T-cells. Results were analyzed using the Mann Whitney U non-parametric test and a compare means test. p values <0.05 were considered statistically significant. Results: The study included 28 MM patients (10 female and 18 male). In all, 11 of the patients underwent APBSCT. The level of Tregs identified as CD4+CD25+FOXP3+ T-cells was higher in the patients that underwent APBSCT (p=0.042). CD200 and PD-1 levels did not significantly differ between the 2 groups (p=0.711 and p=0.404, respectively). There weren't any statistically significant differences in CD200, PD-1, or CD4+CD25+FOXP3+ T-cell levels between the patients that did and did not undergo APBSCT (p>0.05). Conclusion: Treg levels were higher in the patients that underwent APBSCT. Tregs are crucial for the induction and maintenance of peripheral tolerance to self-antigens. In addition, Tregs can suppress immune responses to tumor antigens; however, APBSCT and Treg levels were not correlated with CD200 or PD-1 expression. Relationship of Tregs with prognosis needs to be determined by studies that include larger cohorts. (Turk J Hematol 2011; 28: 107-14)

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“…17 We recently observed that after allo-SCT in myeloma patients, T-regulatory cells expanded faster than conventional CD4 þ cells in BM, and that they expressed mainly CD45RA( À )/CCR7( À ) memory-T-cell phenotype. 18 The number of studied patients and samples are too small to draw definite conclusions, but the figures suggest a rapid increase of activated T and NK cells 1-2 months after treatment, and a decrease of the activated T and NK cells after 3-4 months, whereas the major increase of Tregulatory cells was seen mainly after 6 months. This might be interpreted as a counter-regulatory reaction to the increase of activated T and NK cells.…”

Section: Discussionmentioning

confidence: 96%

Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44+) and T (HLA-DR+) cells

Lioznov

El-Cheikh

Hoffmann

et al. 2009

Bone Marrow Transplant

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We investigated efficacy and toxicity of lenalidomide in 24 heavily pretreated myeloma patients with a median age of 59 years (range: 37-70) and relapse after allo-SCT. Lenalidomide was given at a dose of 15 mg (n ¼ 4), or 25 mg (n ¼ 20), orally once daily on day 1 to day 1 every 28 days, with (n ¼ 20) or without (n ¼ 4) DHAP. The median number of lenalidomide cycles was five (range: 2-17). Major side effects were leukopenia (grade 4: 4%, grade 3: 21% and grade 2: 17%) and thrombocytopenia (grade 3: 17% and grade 2: 29%); infectious complications were observed in 50%. Non-hematological toxicity consisted of muscle cramps (n ¼ 9), fatigue (n ¼ 5) and constipation (n ¼ 2). Mild grade I-II GVHD was seen in three patients. Response was achieved in 66%: CR in 8%, VGPR in 8%, PR in 50% and SD in 13%. The median time to progression was 9.7 months (95% confidence interval (CI): 7.5-11.9), and median OS was 19.9 months (95% CI: 17.3-22.5). Immunomonitoring after lenalidomide showed significant increase of activated NK (NKp44 þ ) and T (HLA-DR þ ) cells, as well as regulatory T cells (CD4 þ , CD25 þ , CD127 lo ), supporting an immunomodulating anti-myeloma effect of lenalidomide.

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CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma following allogeneic stem cell transplantation

Abstract: BackgroundVery little is known about the number and function of immunosuppressive CD4

Cited by 57 publications

References 43 publications

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

The correlation between T regulatory cells and autologous peripheral blood stem cell transplantation in multiple myeloma

Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44+) and T (HLA-DR+) cells

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