scholarly journals The Therapeutic Strategies of Regulatory T Cells in Malignancies and Stem Cell Transplantations

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Rana G. Zaini ◽  
Amani A. Al-Rehaili
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Immune System ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
Treg Cell Function

Regulatory T cells (Treg cells) are considered one of the main dynamic cell types within the immune system. Because Treg cells suppress immune responses, they have potential roles in immunological self-tolerance and may help to maintain immune homeostasis. Promoting Treg cell function and increasing their numbers might be useful in treating autoimmune disorders, as well as preventing allograft rejection. However, studies of mice and humans demonstrate that Treg cells promote cancer progression and suppress antitumor immunity. Therefore, suppressing Treg cell function or reducing their numbers could support the immune system’s response to pathogenic microorganisms and tumors. As a result, there is great interest in investigating the Treg cells role in the treatment of hematological and nonhematological malignancies. Consequently, Treg cells could be a fundamentally important target for pathologies of the immune system. Targeting effector Treg cells could help to distinguish and selectively decrease these cells while preserving other Treg cells needed to suppress autoimmunity. Currently, a promising way to treat malignancies and other autoimmune disorders is stem cell transplantation. Stem cell transplants (SCT) can help to manage the production of Treg cells and also may produce more efficient Treg cells, thereby suppressing clinical disease progression. Specifically, mature T cells within the engrafted stem cells mediate this SCT beneficial effect. During SCT, the recipient’s immune system is replaced with a donor, which allows for improved immune system function. In addition, SCT can protect from disease relapse, as graft-versus-host disease (GvHD) in transplant patients can be protective against cancer recurrence. The current review will define the role of regulatory T cells in treatment of malignancy. Additionally, it will summarize current promising research regarding the utility of regulatory T cells in stem cell transplantation.

Human regulatory T cells in allogeneic stem cell transplantation

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. e82-e92 ◽  
Author(s):  
Sya N. Ukena ◽  
Sarvari Velaga ◽  
Robert Geffers ◽  
Jens Grosse ◽  
Udo Baron ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cell Function ◽  
Time Window ◽  
Tolerance Induction ◽  
Beneficial Effects

Abstract GVHD is still one of the major complications after allogeneic stem cell transplantation. Whereas murine data have clearly shown the beneficial effects of regulatory T cells (Tregs) on the prevention of GVHD, data from the human system are rare. Here, we present a comparative dynamic analysis of CD4+CD25hiCD127lo/− Tregs from patients with and without GVHD analyzing the whole genome profile over the first 6 months after stem cell transplantation, representing the most sensitive time window for tolerance induction. The Treg transcriptome showed a high stability. However, the comparison of Treg transcriptomes from patients with and without GVHD uncovered regulated gene transcripts highly relevant for Treg cell function. The confirmative protein analyses demonstrated a significantly higher expression of granzyme A, CXCR3, and CCR5 in Tregs of immune tolerant patients. These results point to a reduced suppressive function of Tregs from GVHD patients with diminished migration capacity to the target organs.

scholarly journals TRAF3 regulates the effector function of regulatory T cells and humoral immune responses

2013 ◽  
Vol 211 (1) ◽  
pp. 137-151 ◽  
Author(s):  
Jae-Hoon Chang ◽  
Hongbo Hu ◽  
Jin Jin ◽  
Nahum Puebla-Osorio ◽  
Yichuan Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
Antibody Responses ◽  
Effector Memory ◽  
Humoral Immune ◽  
Treg Cell Function

Regulatory T cells (Treg cells) control different aspects of immune responses, but how the effector functions of Treg cells are regulated is incompletely understood. Here we identified TNF receptor–associated factor 3 (TRAF3) as a regulator of Treg cell function. Treg cell–specific ablation of TRAF3 impaired CD4 T cell homeostasis, characterized by an increase in the Th1 type of effector/memory T cells. Moreover, the ablation of TRAF3 in Treg cells resulted in increased antigen-stimulated activation of follicular T helper cells (TFH cells), coupled with heightened formation of germinal centers and production of high-affinity IgG antibodies. Although the loss of TRAF3 did not reduce the overall frequency of Treg cells, it attenuated the antigen-stimulated production of follicular Treg cells (TFR cells). TRAF3 signaling in Treg cells was required to maintain high level expression of inducible co-stimulator (ICOS), which in turn was required for TFR cell generation and inhibition of antibody responses. These findings establish TRAF3 as a mediator of Treg cell function in the regulation of antibody responses and suggest a role for TRAF3 in mediating ICOS expression in Treg cells.

Vaccination with DC/Multiple Myeloma Fusions in Conjunction with Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 578-578
Author(s):  
David Avigan ◽  
Jacalyn Rosenblatt ◽  
Baldev Vasir ◽  
Zekui Wu ◽  
Adam Bissonnette ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Tumor Immunity ◽  
Myeloma Cells ◽  
Post Transplant

Abstract Autologous transplantation results in the transient reversal of tumor mediated tolerance due to the reduction in disease bulk, the depletion of regulatory T cells, and in the increased presence of tumor reactive lymphocytes during the period of lymphopoietic reconstitution. As a result, cancer vaccines are being explored as a means of targeting residual myeloma cells following stem cell transplant. We have developed a cancer vaccine in which patient derived tumor cells are fused with autologous dendritic cells (DCs). In this way multiple tumor antigens are presented in the context of DC mediated costimulation. We are conducting a study in which patients with multiple myeloma (MM) undergo stem cell transplantation followed by vaccination with 3 doses of DC/MM fusions. DCs were generated from adherent mononuclear cells cultured with GM-CSF and IL-4 for 5–7 days and matured with TNFa. DCs strongly expressed costimulatory and maturation markers. Myeloma cells were isolated from bone marrow aspirates and were identified by their expression of CD38, CD138, and/or MUC1. DC and MM cells were fused with polyethylene glycol as previously described and fusion cells were quantified by determining the percentage of cells that coexpress unique DC and myeloma antigens. To date, 19 patients have been enrolled and 18 have completed vaccine generation. Mean yield of the DC and myeloma preparations was 1.84 × 108 and 8.3 × 107 cells, respectively. Mean fusion efficiency was 40% and the mean cell dose was 4.3 × 106 fusion cells. As a measure of their potency as antigen presenting cells, fusion cells prominently stimulated allogeneic T cell proliferation in vitro. Mean stimulation indexes were 12, 57, and 31 for T cells stimulated by myeloma cells, DCs, and fusion cells, respectively. Adverse events judged to be potentially vaccine related included injection site reactions, pruritis, myalgias, fever, chills, and tachycardia. Six patients have completed the follow up period and 3 patients are currently undergoing vaccination. All patients achieved a partial response to transplant. Three patients demonstrated resolution of post-transplant paraprotein levels following vaccination. One patient with highly aggressive disease who experienced disease progression in the early post-transplant period, demonstrated initial response and then stabilization of disease with vaccination. We are examining the effect of transplant and vaccination on measures of cellular immunity, anti-tumor immunity and levels or activated as compared to regulatory T cells. T cell response to PHA mitogen was transiently depressed post-transplant. In contrast, a transient increase was noted post-transplant in mean T cell expression of IFNγ in response to autologous myeloma cell lysate. In preliminary studies, a relative increase in the ratio of activated (CD4/CD25low) to regulatory (CD4/CD25high) T cells was observed. To date, all evaluable patients demonstrated evidence of vaccine stimulated anti-tumor immunity as manifested by a rise in IFNγ expression by CD4 and/or CD8+ T cells following ex vivo exposure to autologous tumor lysate. In this ongoing study, fusion cell vaccination in conjunction with stem cell transplantation has been well tolerated, induced anti-tumor immunity and clinical responses in patients with multiple myeloma.

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