Role of regulatory T cell populations in controlling graft vs host disease

doi:10.1016/j.beha.2011.05.006

Best Practice & Research Clinical Haematology

Volume 24, Issue 3, September 2011, Pages 453-457

https://doi.org/10.1016/j.beha.2011.05.006 Get rights and content

Immune function is critical in health and disease. The control and regulation of immune reactions is an area of intense investigation that has important implications for allogeneic hematopoietic cell transplantation. Immune reactions are regulated in a number of important ways. Compartmentalization of immune responses and the production of both pro-inflammatory and anti-inflammatory cytokines play a major role. More recently several populations of T cells that regulate immune responses termed regulatory T cells have been identified. This manuscript will focus on CD4⁺CD25⁺FoxP3⁺ natural regulatory T cells (T_reg) and αβTCR⁺CD4⁺NK1.1⁺ natural killer T (NK-T) cells which both suppress graft vs host disease but appear to function by distinct mechanisms.

Highlights

► Immune reactions are controlled by a number of mechanisms including specific T cells. ► Regulatory T cells prevent GVHD. ► Clinical translation is ongoing.

Section snippets

Funding

Source of Funding: Studies discussed here were funded by NIH award P01 CA049605 and HL075462.

Conflict of interest

There are no conflicts to report.

References (16)

P.A. Taylor et al.
The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality
Blood
(2002)
S.C. Jones et al.
Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-versus-leukemia response
Biol Blood Marrow Transplant
(2003)
V.H. Nguyen et al.
In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation
Blood
(2007)
V.H. Nguyen et al.
The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation
Blood
(2008)
D.B. Leveson-Gower et al.
Low doses of natural killer T cells provide protection from acute graft-versus-host disease via an IL-4 dependent mechanism
Blood
(2011)
Y. Reisner et al.
Transplantation tolerance induced by “mega dose” CD34+ cell transplants
Exp Hematol
(2000)
M. Di Ianni et al.
Tregs prevent GvHD and promote immune reconstitution in HLA-haploidentical transplantation
Blood
(2011)
R. Hoffmann et al.
Donor type CD4⁺CD25⁺ regulatory T cells suppress lethal acute graft-versus-hosti disease after allogeneic bone marrow transplantation
J Exp Med
(2002)

There are more references available in the full text version of this article.

Cited by (7)

Regulatory T Cell Therapy in Transplantation
2017, Kidney Transplantation, Bioengineering, and Regeneration: Kidney Transplantation in the Regenerative Medicine Era
Receiving a kidney transplant currently requires patients to commit to life-long immunosuppression therapy. The combination of immunosuppressive drugs currently taken by transplant recipients often does achieve the right degree of immunosuppression. While over-immunosuppression is associated with increased risks of infection and malignancies, under-immunosuppression leads to graft rejection, reduced graft function over time, and even graft loss. Moreover, many commonly used immunosuppressive drugs are ironically nephrotoxic. Therefore, a more precise and less toxic approach to controlling alloimmune response against grafts is needed. The immune system has its own built-in control to prevent the attacking of one’s own healthy organs. An essential component of immune self-tolerance is regulatory T cells (Tregs). Tregs are a special lineage of cells dedicated to preventing unwanted immune response, dampening inflammation, and restoring immune homeostasis after immune activation. Research demonstrates that Tregs also control alloimmune responses and Tregs can be used therapeutically to induce transplantation tolerance in preclinical models. Treg cell therapy harnesses the natural ability of immune self-regulation and has the potential to achieve more robust and specific control of antigraft responses. Translating Treg cell therapy to the clinic began in the late 2000s with 7 phase 1 clinical trials in graft-versus-host disease, type 1 diabetes, and liver transplantation published by mid-2016. In this chapter, we summarize preclinical developments, translational efforts, and clinical implementation of Treg cell therapy in transplantation.
National Institutes of Health State of the Science Symposium in Therapeutic Apheresis: Scientific Opportunities in Extracorporeal Photopheresis
2015, Transfusion Medicine Reviews
Citation Excerpt :
Th17 cells are emerging as the major effector cells in cellular-based autoimmunity and in GVHD [26]. Treg cells appear to play a key role in the maintenance of immune tolerance and homeostasis including in GVHD [27]. Evaluation of circulating T-cell subsets pre-ECP and post-ECP has demonstrated an increase in CD25 + CD4 + Foxp3 Treg cells and IL-10, accompanied by a decrease in Th1, Th17 cells, and interferon γ (IFNγ) [28] (Figure).
The clinical use of extracorporeal photopheresis (ECP) for accepted indications such as graft-versus-host disease, transplant rejection, and cutaneous T-cell lymphoma continues to increase. Expanded applications for ECP, such as the treatment of select autoimmune diseases, are being explored. Extracorporeal photopheresis's capacity to both immunotolerize in the autoreactive setting, while immunizing against a lymphoma is unusual and suggestive of a unique mechanism. It is likely that ECP's induction of dendritic cells is key to its efficacy in both of these settings, but exactly how ECP impacts other immune components and their interactions is not fully understood. Further basic science research is necessary to elucidate how these dissimilar cellular activities are functionally integrated. On the clinical side, collaborative multicenter trials designed to recognize the principal variables controlling therapeutic responses and improve prognostic indicators may enable tailoring devices, treatment schedules, and doses to the needs of the individual patients or diseases. This review describes our current understanding of how ECP influences the immune system, reviews the existing clinical applications of ECP, and explores areas for future basic science and clinical research as presented at the National Institutes of Health State of the Science Symposium in Therapeutic Apheresis in November 2012.
Selective depletion of FOXP3high cells by Fas-Fas-L-induced apoptosisoccurs in CD4+CD25+-enriched populations during repeated expansion
2013, Cytotherapy
Citation Excerpt :
The seminal work of Sakaguchi et al. (1) established the role of regulatory T cells (Tregs) in maintaining immunological self-tolerance. The ability of these cells to modulate immune responses has suggested the possibility of the use of isolated and/or expanded Tregs for the prevention or therapy of autoimmune or alloimmune diseases (2–4). In murine models, Tregs effectively suppressed undesirable immune responses in autoimmune diseases, abrogated stem cell transplant related graft-versus-host disease and prevented transplant arteriosclerosis in a humanized mouse system (5–8).
Expansion of anti-CD25 bead-isolated human Tregs culture has paradoxically resulted in reduced suppressive activity, but the mechanism(s) responsible for these observations are poorly defined.
Magnetic-bead isolated human CD25⁺ cells were expanded with anti-CD3/CD28 beads and high doses of rhIL-2. Detection of Fas and Fas ligand (Fas-L) expression, activation of Caspase 8, cell proliferation and cytokine production was evaluated by multi-color fluorescence-activated cell sorting analysis. The role of Fas–Fas-L–mediated cell death was dissected through the use of agonist or antagonist monoclonal antibodies directed at Fas and Fas-L.
Repeated expansion of bead-enriched CD4⁺CD25⁺ cells generated a cellular product with markedly reduced suppressive activity and with significantly increased CD8⁺ T cells and CD4⁺ T cells producing interferon-γ and/or interleukin-2. We showed that Fas–Fas-L–mediated apoptosis of CD4⁺FOXP3^high cells and rapid cell-cycling of CD8⁺ T cells were collectively responsible for the reduced proportion of CD4⁺FOXP3^high cells in expanded cultures. The depletion of CD4⁺FOXP3^high cells and activation of Caspase 8 in CD4⁺FOXP3^high cells was attenuated by Fas antagonist antibody, ZB4, in short-term culture. However, the loss of CD4⁺FOXP3^high cells during expansion was not prevented by either Fas or Fas-L antagonist antibodies.
Taken together, the data show that Fas–Fas-L–mediated apoptosis may limit the expansion of anti-CD25 bead-isolated cells in vitro.
Invariant natural killer T cells in hematopoietic stem cell transplantation: Killer choice for natural suppression
2016, Bone Marrow Transplantation
Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory t cells without diminishing antiviral and antileukemic activity
2014, Clinical Cancer Research
Prevention of graft-vs.-host disease
2012, Expert Opinion on Pharmacotherapy

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Best Practice & Research Clinical Haematology

Highlights

Section snippets

Funding

Conflict of interest

References (16)

The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality

Blood

Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-versus-leukemia response

Biol Blood Marrow Transplant

In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation

Blood

The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation

Blood

Low doses of natural killer T cells provide protection from acute graft-versus-host disease via an IL-4 dependent mechanism

Blood

Transplantation tolerance induced by “mega dose” CD34+ cell transplants

Exp Hematol

Tregs prevent GvHD and promote immune reconstitution in HLA-haploidentical transplantation

Blood

Donor type CD4⁺CD25⁺ regulatory T cells suppress lethal acute graft-versus-hosti disease after allogeneic bone marrow transplantation

J Exp Med

Cited by (7)

Regulatory T Cell Therapy in Transplantation

National Institutes of Health State of the Science Symposium in Therapeutic Apheresis: Scientific Opportunities in Extracorporeal Photopheresis

Selective depletion of FOXP3<sup>high</sup> cells by Fas-Fas-L-induced apoptosisoccurs in CD4<sup>+</sup>CD25<sup>+</sup>-enriched populations during repeated expansion

Invariant natural killer T cells in hematopoietic stem cell transplantation: Killer choice for natural suppression

Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory t cells without diminishing antiviral and antileukemic activity

Prevention of graft-vs.-host disease

14Role of regulatory T cell populations in controlling graft vs host disease

Highlights

Section snippets

Funding

Conflict of interest

Blood

Biol Blood Marrow Transplant

Blood

Blood

Blood

Exp Hematol

Blood

Donor type CD4+CD25+ regulatory T cells suppress lethal acute graft-versus-hosti disease after allogeneic bone marrow transplantation

J Exp Med

14
Role of regulatory T cell populations in controlling graft vs host disease

Donor type CD4⁺CD25⁺ regulatory T cells suppress lethal acute graft-versus-hosti disease after allogeneic bone marrow transplantation