CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation

Edinger, Matthias; Hoffmann, Petra; Ermann, Joerg; Drago, Kathryn; Fathman, C. Garrison; Strober, Samuel; Negrin, Robert S.

doi:10.1038/nm915

Cited by 1,171 publications

(998 citation statements)

References 39 publications

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“…2A and B). These data are in line with previous studies defining a protective role for nTreg in GVHD [1,16]. In marked contrast, we did not observe any protective effect in mice receiving iTreg ( Fig.…”

Section: Resultssupporting

confidence: 94%

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

et al. 2009

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Induced antigen-specific Foxp3 1 T cells (iTreg) are being discussed as a promising alternative to polyclonal natural Foxp3 1 T cells (nTreg) for cell-based therapies, particularly to achieve transplantation tolerance. Using Foxp3eGFP-reporter mice, we here establish an efficient protocol to induce and expand alloantigen-specific iTreg from Foxp3 À CD4 1 T cells with cluster-disrupted DC. These iTreg were mainly CD62L 1 and showed efficient suppressive activity in vitro. However, in contrast to nTreg, adoptively transferred iTreg entirely failed to prevent lethal graft versus host disease (GVHD). Within irradiated recipients, the majority of adoptively transferred Foxp3 1 iTreg, but not Foxp3 1 nTreg quickly reverted to Foxp3 À CD4 1 T cells. We therefore suggest that therapeutic approaches to treat GVHD should rely on nTreg, whereas the use of de novo alloantigen-induced iTreg should be handled with caution since the stability of the regulatory phenotype of the iTreg could be of major concern.Key words: Animal models . Dendritic cells . Graft rejection . Regulatory T cells See accompanying article by commentary by Edinger IntroductionRecent advances have demonstrated that adoptively transferred exogenous Treg can inhibit graft versus host disease (GVHD) [1][2][3]. However, the availability of sufficient numbers of donor Treg for cell-based therapies remains limited [4]. Besides the in vitro expansion of nTreg [5], an obvious approach to solve this problem would be the de novo induction and expansion of Foxp3 1 Treg from abundant naïve CD4 1 T cells with recipient alloantigens [6,7]. Instead of mediating unspecific suppression, such alloantigen-induced Treg potentially could provide the advantage of antigen-specific regulation, thereby reducing the risk of disease relapse and infections [8]. Here, we present an efficient protocol to induce Foxp3 1 Treg by the use of clusterdisrupted allogeneic DC. Such allo DC-induced iTreg were functionally active in vitro and displayed a stable regulatory phenotype upon adoptive transfer into untreated syngeneic recipients. However, when used in experimental acute GVHD, these cells quickly lost Foxp3 expression and, in contrast to nTreg, did not show any protective effect. SHORT COMMUNICATION Results and discussionTo define conditions suited for the de novo induction of alloantigen-specific iTreg, we isolated Foxp3 À CD4 1 T cells from C57BL/6 Foxp3EGFP mice and co-cultured them with BM-derived allogeneic BALB/c DC that were either matured by application of LPS or via ''cluster-disruption'' (CD-DC). Disruption of the Ecadherin-mediated cell-cell contacts induces DC maturation through mechanisms distinct from TLR signaling [9]. Since antigen-loaded CD-DC have been shown to induce tolerance in mice after i.v. injection [9] we established a protocol that allowed the conversion of naïve to Foxp3 expressing cells in vitro in the presence of allogeneic but not syngeneic CD-DC. When compared with LPS-matured DC, CD-DC showed equally high expression of MHC class II, but diminished up...

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Section: Resultssupporting

confidence: 94%

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

et al. 2009

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“…80 In mouse BMT models, naturally occurring donor-derived Tregs suppress the proliferation of conventional T cells, prevent GVHD and preserve GVL effects depending on the ratio of effector T cells to Tregs. [81][82][83][84][85][86] Furthermore, viral immunity is preserved in the presence of Tregs after allogeneic HCT. 87 The mechanisms for suppression in the context of GVHD remain completely unknown.…”

Section: Sensors Of Gvhdmentioning

confidence: 99%

New perspectives on the biology of acute GVHD

Paczesny

Hanauer

Sun

et al. 2009

Bone Marrow Transplant

157

126

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The use of allogeneic hematopoietic cell transplantation (HCT) has increased as new techniques have been developed for transplantation in patients who previously would not have been considered HCT candidates. However, its efficacy continued to be limited by the development of frequent and severe acute GVHD. The complex and intricate pathophysiology of acute GVHD is a consequence of interactions between the donor and host innate and adaptive immune responses. Multiple inflammatory molecules and cell types are implicated in the development of GVHD that can be categorized as:(1) triggers that initiate GVHD by therapy-induced tissue damage and the antigen disparities between host and graft tissue; (2) sensors that detect the triggers, that is, process and present alloantigens; (3) mediators such as T-cell subsets (naive, memory, regulatory, Th17 and natural killer T cells) and (4) the effectors and amplifiers that cause damage of the target organs. These multiple inflammatory molecules and cell types that are implicated in the development of GVHD have been described with models that use stepwise cascades. Herein, we provide a novel perspective on the immunobiology of acute GVHD and briefly discuss some of the outstanding questions and limitations of the model systems.

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“…Several studies have tried to solve this dilemma. It has been shown that CD4 + Treg from the donor or recipient can control GVHD after BM transplantation [21,[55][56][57][58]. In previous studies, we have found that donor DN-Treg could suppress donor CD8 + T cells, which caused GVHD in a single MHC-mismatched model [32].…”

mentioning

confidence: 90%

Donor double‐negative Treg promote allogeneic mixed chimerism and tolerance

Wang

et al. 2007

Eur J Immunol

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Bone marrow (BM) transplantation is an efficient approach to develop donor-specific tolerance and prevent chronic rejection. Allogeneic BM transplantation is limited by donor T cell-mediated graft-versus-host disease, requirement of cytoreduction and high numbers of BM cells. In addition of these drawbacks, recent studies demonstrate that not only T cells, but also NK cells can mediate BM rejection, and long-term mixed chimerism depends on NK cell tolerance. Thus, NK cell is another potential barrier against engraftment of BM and an important target in efforts to induce transplant tolerance. We have previously identified a novel type of Treg with the phenotype TCRab + CD3 + CD4 -CD8 -(double-negative, DN). We and others have demonstrated that DN-Treg can effectively suppress anti-donor T cell responses. In this study, we found that donor-derived DN-Treg can suppress NK cell-mediated allogeneic BM graft rejection in both parent-to-F1 and fully MHC-mismatched BM transplantation models. Perforin and FasL in DN-Treg play important roles in the suppression of NK cells. Furthermore, adoptive transfer of DN-Treg can promote a stable mixed chimerism and donor-specific tolerance without inducing graft-versus-host disease. These results demonstrate a potential approach to control innate immune responses and promote allogeneic BM engraftment. IntroductionEstablishing donor-specific transplant tolerance is beneficial for several reasons: it can prevent chronic rejection and avoid side effects related to long-term immunosuppressive drug treatment. It also can help patients to preserve their own natural immunity against infections and tumors. Achieving mixed chimerism via BM transplantation is an efficient approach that directs the immune system to regard the donor as 'self'. By generating specific immunologic tolerance to donor transplants, chronic rejection as well as the need for ongoing immunosuppression can be avoided [1][2][3].Rejection of MHC-mismatched allografts is largely mediated by a recipient's CD4 + and CD8 + T cells. Recent studies, however, have demonstrated that NK cells are another potential barrier in allograft rejection and tolerance [4][5][6][7]. Furthermore, studies have shown that NK cells can mediate BM rejection [8,9]. This notion has been well addressed in the hybrid resistance model, in which parental BM cells, not solid organs, are vigorously rejected by an F1 hybrid [10,11]. This rejection is mediated solely by a recipient's NK cells, not by T cells, NKT cells or B cells [12][13][14] [20,21].In recent studies, we found that TCRab + CD3 + CD4 -CD8 -(double-negative, DN) T cells possess immuneregulatory functions and play an important role in the development of tolerance post-transplantation [22][23][24][25]. We have demonstrated that mouse DN-Treg specifically can eliminate activated syngeneic anti-donor CD4 + T cells, CD8 + T cells, and B cells [22,23,25,26]. Furthermore, adoptive transfer of DN-Treg leads to significant prolongation of donor-specific skin and heart allografts in a single MHC-mis...

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CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation

Cited by 1,171 publications

References 39 publications

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

New perspectives on the biology of acute GVHD

Donor double‐negative Treg promote allogeneic mixed chimerism and tolerance

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CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation

Cited by 1,171 publications

References 39 publications

Alloantigen‐specific de novo‐induced Foxp3+ Treg revert in vivo and do not protect from experimental GVHD

Alloantigen‐specific de novo‐induced Foxp3+ Treg revert in vivo and do not protect from experimental GVHD

New perspectives on the biology of acute GVHD

Donor double‐negative Treg promote allogeneic mixed chimerism and tolerance

Contact Info

Product

Resources

About

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD