Immunomodulation after allogeneic bone marrow transplantation by CD4+CD25+ regulatory T cells

Hoffmann, Petra; Boeld, Tina J.; Piseshka, Biserka; Edinger, Matthias

doi:10.1016/j.micinf.2005.03.035

Cited by 7 publications

(6 citation statements)

References 43 publications

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“…ϩ and CD8 ϩ effector T cells (22,24,(37)(38)(39)(40). In allogeneic transplantation, only donor CD4 ϩ 25 ϩ regulatory T cells and not host can provide protection against GVHD (22).…”

Section: Discussionmentioning

confidence: 99%

Induction of FoxP3+CD4+25+ Regulatory T Cells Following Hemopoietic Stem Cell Transplantation: Role of Bone Marrow-Derived Facilitating Cells

Taylor

Shinde-Patil

Cohick

et al. 2007

The Journal of Immunology

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The establishment of donor cell lineages following allogeneic bone marrow transplantation is frequently associated with the development of graft-vs-host disease (GVHD). The identification of cell populations that are capable of supporting allogeneic stem cell (SC) engraftment and the induction of tolerance without inducing GVHD could expand the use of this therapy. CD8+TCR− facilitating cells (FC) have been shown to promote allogeneic SC engraftment with resulting transplantation tolerance across complete MHC barriers without inducing GVHD. Although donor reconstitution in SC plus FC recipients is associated with the induction of regulatory T cell-associated factors, it is not known whether an induction of regulatory T cells and subsequent tolerance is a direct effect of the FC. The current study demonstrates that 1) SC plus FC transplantation results in the induction of donor CD4+25+ regulatory T cells and that FC are present in the spleen of recipients before the induction of these cells, 2) activation of FC with CpG-oligodeoxynucleotide promotes CD4+25− T cell differentiation into CD4+25+ regulatory T cells in vitro, as demonstrated by cytokine and forkhead/winged helix transcription factor (FoxP3) gene and protein expression, and 3) direct contact between FC and CD4+25− T cells is required for FoxP3+CD4+25+ regulatory T cell induction and is dependent on CD86 expression on FC. This is the first report to demonstrate a mechanism for FC in the induction of regulatory T cells following allogeneic SC plus FC transplantation. The transplantation of donor FC may provide an alternative approach to permit clinical SC engraftment and induction of transplantation tolerance in the future.

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“…ϩ and CD8 ϩ effector T cells (22,24,(37)(38)(39)(40). In allogeneic transplantation, only donor CD4 ϩ 25 ϩ regulatory T cells and not host can provide protection against GVHD (22).…”

Section: Discussionmentioning

confidence: 99%

Induction of FoxP3+CD4+25+ Regulatory T Cells Following Hemopoietic Stem Cell Transplantation: Role of Bone Marrow-Derived Facilitating Cells

Taylor

Shinde-Patil

Cohick

et al. 2007

The Journal of Immunology

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“…Since one obstacle in clinical application is low T reg frequency, many of these clinical trials have relied upon ex vivo expanded T regs to generate large cell numbers to be transplanted. Furthermore, experimental models demonstrated the need for a high T reg :T effector (T eff ) ratio to promote therapeutic benefit (43, 47–49). Several groups have pioneered in vitro T reg expansion protocols (32, 33) (10, 50–53) by polyclonal stimulation of autologous T regs in the presence of high-dose IL-2.…”

Section: Adoptive Treg Therapy For Prevention Of Gvhdmentioning

confidence: 99%

Adoptive T Regulatory Cell Therapy for Tolerance Induction

2015

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There is a clear need to develop strategies to induce tolerance without the need of chronic immunosuppression in transplant recipient and in patients with autoimmunity. Adoptive T regulatory cell (Treg) therapy offers the potential of long-lasting protection. However, based on results of clinical trials so far with ex vivo expanded autologous Tregs in type 1 diabetic (T1D) patients, it seems unlikely that single immunotherapy with Treg infusion without immunomodulation regimens that promote stable donor Treg engraftment and persistence would afford truly significant clinical benefit. Combination therapies could provide improved outcomes with consideration of the fundamental factors required for Treg generation, homeostasis, and function to promote long-term donor Treg persistence to provoke beneficial therapeutic outcomes.

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“…Very little is known about the role of T regs in allogeneic HSCT and to what extent they are affected by immune reconstitution (19) but, in animal models, their adoptive transfer controls graft-vs.-host disease (GvHD) (20)(21)(22)(23)(24) and induce specific tolerance to bone marrow (BM) allografts (25,26). How RIC determines HvG tolerance and whether this involves T reg function and specificity are unknown.…”

mentioning

confidence: 99%

Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment

Weng

Dyson

Dazzi

2007

Proc. Natl. Acad. Sci. U.S.A.

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Low-or reduced-intensity conditioning regimens for allogeneic hemopoietic stem cell transplantation are effective at establishing donor hematopoietic engraftment and host-vs.-graft (HvG) tolerance. We investigated the mechanisms of HvG tolerance induction and maintenance in an animal model in which transplantation of sublethally irradiated female recipients with bone marrow (BM) from syngeneic male donors produces mixed chimerism. Splenocytes from chimeric mice inhibited HY-specific CD8 ؉ T cell responses both in vitro and in vivo, and their adoptive transfer facilitated donor hematopoietic engraftment. These properties were contained within the CD4 ؉ CD25 ؉ population. The conditioning protocol alone led to a proportional expansion of regulatory T cells (T regs), but the inhibitory activity was induced only if male BM was infused. The administration of anti-CD25-depleting antibodies to conditioned recipients at time of BM transplantation prevented donor-recipient chimerism but did not affect engraftment if performed after the establishment of chimerism, thus indicating that recipient Tregs are required for the generation but not the maintenance of HvG tolerance. We conclude that donor-specific Tregs of recipient origin are recruited when the donor antigens are present during reduced-intensity conditioning-induced Treg expansion.host vs. graft ͉ reduced-intensity conditioning ͉ stem cell transplantation ͉ tolerance A llogeneic hemopoietic stem cell transplantation (HSCT) is a well established treatment modality for malignant and nonmalignant diseases (1). The conventional approach to condition the patient with fully myeloablative regimens has recently been reconsidered in light of the therapeutic goals (2) and led to the development of low-or reduced-intensity conditioning (RIC) regimens whereby the role of conditioning is confined to the establishment of mixed hemopoietic chimerism and the consequent host-vs.-graft (HvG) tolerance (3, 4). Evidence exists that such approaches could also be used before solid organ transplantation (5) and to prevent the rejection of genetically modified cells (6).The coexistence of donor and recipient hematopoiesis after RIC regimens creates durable HvG tolerance with no need for long-term immunosuppression. Despite the importance of central and peripheral deletional tolerance in the establishment of mixed chimerism (7), active regulation has emerged as being central (8,9). Natural regulatory T (T reg ) cells are a subpopulation of thymus-derived CD4 ϩ T cells that constitutively express CD25 (10, 11) and the forkhead box P3 (FoxP3) gene product (12). They play a crucial role in peripheral tolerance, susceptibility to autoimmune disease (13), and tumor immunity (14), as well as in the induction of transplantation tolerance (15-18).Very little is known about the role of T regs in allogeneic HSCT and to what extent they are affected by immune reconstitution (19) but, in animal models, their adoptive transfer controls graft-vs.-host disease (GvHD) (20-24) and induce specific toleranc...

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Immunomodulation after allogeneic bone marrow transplantation by CD4+CD25+ regulatory T cells

Cited by 7 publications

References 43 publications

Induction of FoxP3+CD4+25+ Regulatory T Cells Following Hemopoietic Stem Cell Transplantation: Role of Bone Marrow-Derived Facilitating Cells

Induction of FoxP3+CD4+25+ Regulatory T Cells Following Hemopoietic Stem Cell Transplantation: Role of Bone Marrow-Derived Facilitating Cells

Adoptive T Regulatory Cell Therapy for Tolerance Induction

Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment

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