Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation

Hoffmann, Petra; Ermann, Joerg; Edinger, Matthias; Fathman, C. Garrison; Strober, Samuel

doi:10.1084/jem.20020399

Cited by 1,009 publications

(787 citation statements)

References 48 publications

(94 reference statements)

Supporting

Mentioning

744

Contrasting

Unclassified

Order By: Relevance

“…In this study, upregulation of Treg genes was associated with the absence of GvHD despite donor effector cell administration. 48 All these data including those on the prevention of GvHD 5,6 and our findings highlight the in vivo donor Treg induction/expansion as a promising approach to prevent the deleterious alloreactivity after HC transplantation.…”

Section: Discussionsupporting

confidence: 51%

“…1 Recently, active suppression by CD4 þ CD25 þ regulatory T cells (Treg) has been extensively explored as a mechanism involved in limiting autoimmunity 2,3 as well as a way to induce transplantation tolerance. 4 Thus, CD4 þ CD25 þ Treg cells have been shown to prevent acute graft-versus-host disease (GvHD), 5,6 a frequent complication of allogeneic hematopoietic cell (HC) transplantation. Expression of CD25 is shared by different CD4 þ Treg subsets including CD4 þ CD25 þ 'suppressive' T cells, which act by cell contact-dependent mechanisms, 3,7 IL-10-producing T regulatory type 1 (Tr1) cells 8 and TGF-b-producing Th3 cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

et al. 2005

View full text Add to dashboard Cite

Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-bdependent donor CD4 þ CD25 þ T-cell expansion. Such cells have a regulatory phenotype (CD62L high and intracellular CTLA-4 þ ), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.

show abstract

Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Recent 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].…”

Section: Introductionmentioning

confidence: 99%

“…This may be due the fact that some Foxp3 negative cells are also of a regulatory phenotype, such as T regulatory 1 cells [15]. Next, we examined whether these alloantigen-specific iTreg could interfere with the outcome of GVHD as had been described for nTreg [1]. Lethally irradiated (2 Â 4 Gy) BALB/c recipients were transplanted with 5 Â 10 6 Tcell-depleted BM (TCD-BM) plus 5 Â 10 5 MACS-purified Tconv alone, or together with 5 Â 10 5 FACS-sorted nTreg or iTreg.…”

mentioning

confidence: 99%

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

et al. 2009

View full text Add to dashboard Cite

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...

show abstract

“…In murine disease models, adoptively transferred Treg prevent, and in some cases, even cure autoimmunity [2,3]. In addition, they protect from graft rejection after allogeneic organ transplantation [4] as well as from graft-versus-host disease after MHCmismatched stem cell transplantation [5][6][7][8]. Recently, a limited number of Phase I clinical trials exploring the adoptive transfer of Treg have been initiated and several additional trials in various clinical settings are in preparation [9,10].…”

mentioning

confidence: 99%

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

et al. 2009

Self Cite

View full text Add to dashboard Cite

The adoptive transfer of CD4 1 CD25 1 natural regulatory T cells (Treg) is a promising strategy for the treatment of autoimmune diseases and the prevention of alloresponses after transplantation. Clinical trials exploring this strategy require efficient in vitro expansion of this rare cell population. Protocols developed thus far rely on high-grade purification of Treg prior to culture initiation, a process still hampered by the lack of Treg cell-specific surface markers. Depletion of CD127 1 cells was shown to separate activated conventional T cells from natural Treg cell populations allowing the isolation of highly enriched FOXP3 1 cells with all functional and molecular characteristics of natural Treg. Here, we demonstrate that upon in vitro expansion, CpG methylation in a conserved region within the FOXP3 gene locus increased in CD4 1 CD25 1 CD127 low Treg, correlating with loss of FOXP3 expression and emergence of pro-inflammatory cytokines. Further analysis identified CD45RA À FOXP3 1 memory-type Treg as the main source of converting cells, whereas CD45RA 1 FOXP3 1 Treg from the same donors showed no conversion within 3 wk of in vitro expansion. Thus, Treg cell lineage differentiation does not seem to represent a final fate decision, as natural Treg can lose their cell-type-specific characteristics after repetitive TCR stimulation.Key words: Cellular therapy . Immune regulation . Treg Supporting Information available online Introduction CD4 1 CD25 1 Treg are pivotal for the maintenance of peripheral self-tolerance and imbalances in this T-cell compartment have been shown to contribute to various autoimmune diseases [1]. In murine disease models, adoptively transferred Treg prevent, and in some cases, even cure autoimmunity [2,3]. In addition, they protect from graft rejection after allogeneic organ transplantation [4] as well as from graft-versus-host disease after MHCmismatched stem cell transplantation [5][6][7][8]. Recently, a limited number of Phase I clinical trials exploring the adoptive transfer of Treg have been initiated and several additional trials in various clinical settings are in preparation [9,10]. Prerequisites for the initiation of such trials are (i) the availability of efficient in vitro expansion protocols for this rare cell population and (ii) the ability to unequivocally identify Treg to avoid contamination of 1088Treg cultures with potentially harmful conventional effector T cells (Tconv). While efficient cell culture protocols have recently been established by us and others for the polyclonal as well as antigen-specific Treg cell expansion [11][12][13], the search for an exclusive surface marker for Treg is still ongoing.Contrary to earlier reports, human CD4 1 CD25 high Treg in adult peripheral blood have recently been shown to comprise not only (self-)antigen-experienced, CD45RA À central and effector memory cells, but also a subpopulation of CD45RA 1 naïve recent thymic emigrants [14,15]. We previously demonstrated that these CD45RA 1 CD4 1 CD25 high T cells (RA 1 Treg) homogen...

show abstract

Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation

Cited by 1,009 publications

References 48 publications

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

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

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

Contact Info

Product

Resources

About

Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation

Cited by 1,009 publications

References 48 publications

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

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

Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation

Contact Info

Product

Resources

About

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

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation