Inhibition of the Alloimmune Response through the Generation of Regulatory T Cells by a MHC Class II-Derived Peptide

Zang, Weiping; Lin, Marvin; Kalache, Safa; Zhang, Nan; Krüger, Bernd; Waaga-Gasser, Ana Maria; Grimm, Martin; Hancock, Wayne W.; Heeger, Peter S.; Schröppel, Bernd; Murphy, Barbara

doi:10.4049/jimmunol.181.11.7499

Cited by 10 publications

(8 citation statements)

References 45 publications

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“…PD-L1, Thy1.2, and CD25 antibodies. Anti-mouse PD-L1 (10F.9G2), antiThy1.2 (30H12), anti-CD25 (PC-61.5.3), and their respective isotype controls have been described previously (14,73,74).…”

Section: Figurementioning

confidence: 99%

Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation

Flutter¹,

Edwards²,

Fallah-Arani³

et al. 2010

J. Clin. Invest.

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Allogeneic blood or BM transplantation (BMT) is the most commonly applied form of adoptive cellular therapy for cancer. In this context, the ability of donor T cells to respond to recipient antigens is coopted to generate graft-versus-tumor (GVT) responses. The major reason for treatment failure is tumor recurrence, which is linked to the eventual loss of functional, host-specific CTLs. In this study, we have explored the role of recipient antigen expression by nonhematopoietic cells in the failure to sustain effective CTL immunity. Using clinically relevant models, we found that nonhematopoietic antigen severely disrupts the formation of donor CD8 + T cell memory at 2 distinct levels that operate in the early and late phases of the response. First, initial and direct encounters between donor CD8 + T cells and nonhematopoietic cells blocked the programming of memory precursors essential for establishing recall immunity. Second, surviving CD8 + T cells became functionally exhausted with heightened expression of the coinhibitory receptor programmed death-1 (PD-1). These 2 factors acted together to induce even more profound failure in long-term immunosurveillance. Crucially, the functions of exhausted CD8 + T cells could be partially restored by late in vivo blockade of the interaction between PD-1 and its ligand, PD-L1, without induction of graft-versus-host disease, suggestive of a potential clinical strategy to prevent or treat relapse following allogeneic BMT.

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“…PD-L1, Thy1.2, and CD25 antibodies. Anti-mouse PD-L1 (10F.9G2), antiThy1.2 (30H12), anti-CD25 (PC-61.5.3), and their respective isotype controls have been described previously (14,73,74).…”

Section: Figurementioning

confidence: 99%

Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation

Flutter¹,

Edwards²,

Fallah-Arani³

et al. 2010

J. Clin. Invest.

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“…Interestingly, previous studies have demonstrated that a MHC class II-derived soluble peptide, HLA-DQA1, inhibits alloimmune responses by binding to the host MHC class II molecule outside of the MHC-binding groove [24]. This peptide altered T cell-APC interaction, promoted host APC apoptosis [25], [26] and induced Treg cells [27]. These interesting studies, though with similar transplantation outcomes, were conducted using totally different approaches from ours.…”

Section: Discussionmentioning

confidence: 59%

Manipulating IL-2 Availability Amid Presentation of Donor MHC Antigens Suppresses Murine Alloimmune Responses by Inducing Regulatory T Cells

Zhang

Dai

et al. 2010

PLoS ONE

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BackgroundMajor histocompatibility complex (MHC) antigens are important for alloimmune responses as well as immune tolerance. Previous studies have shown that presentation of donor MHC antigens by donor-specific transfusion prior to or upon transplantation promotes transplant tolerance induced by other agents. However, it is unclear whether presentation of donor MHC antigens by DNA vaccination induces long-term allograft survival.Methodology/Principal FindingsWe investigated whether presentation of MHC class-II and/or class-I donor antigens by DNA vaccination suppresses alloimmune responses and promotes long-term allograft acceptance. We initially found that presentation of both MHC donor antigens by DNA vaccination itself prior to transplantation fails to significantly prolong islet allograft survival in otherwise untreated mice. However, islet allograft survival was significantly prolonged when MHC class-II DNA vaccination was accompanied with IL-2 administration (MHCII + IL-2) while MHC class-I DNA vaccination was followed by IL-2 and subsequent neutralizing anti-IL-2 treatments (MHCI + IL-2/anti-IL-2). Especially, this protocol promoted long-term allograft survival in the majority of recipients (57%) when combined with low doses of rapamycin post-transplantation. Importantly, MHCII + IL-2 induced FoxP3+ Treg cells in both spleens and grafts and suppressed graft-infiltrating CD4+ cell proliferation, whereas MHCI + IL-2/anti-IL-2 mainly inhibited graft-infiltrating CD8+ cell proliferation and donor-specific CTL activity. The combined protocol plus rapamycin treatment further reduced both CD4+ and CD8+ T cell proliferation as well as donor-specific CTL activity but spared FoxP3+ Treg cells. Depleting CD25+ Treg cells or adoptive transfer of pre-sensitized CD8+ T cells abolished this long-term allograft survival.Conclusions/SignificanceManipulating IL-2 availability during presentation of MHC class-II and class-I donor antigens by DNA vaccination pre-transplantation induces Treg cells, suppresses alloimmune responses and promotes long-term allograft survival.

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“…Our data clearly shows that iTregs not activated by cognate Ag were unable to expand and were ineffective in the prevention of GVHD. Along this line, Sela et al showed that DC-induced, alloAg-specific iTregs are capable of preventing GVHD (36). However, the therapeutic efficacy of their iTregs was lower than HY-specific iTregs used in our current study but higher than polyclonal iTregs used in other studies (27–29), indicating that the efficacy directly correlates with the frequency of alloreactive cells among different types of iTregs.…”

Section: Discussionmentioning

confidence: 99%

HY-Specific Induced Regulatory T Cells Display High Specificity and Efficacy in the Prevention of Acute Graft-versus-Host Disease

Heinrichs

Haarberg

et al. 2015

The Journal of Immunology

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Naturally derived regulatory T cells (nTregs) may prevent graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. However, clinical application of nTregs has been severely hampered by their scarce availability and non-selectivity. To overcome these limitations, we took alternative approaches to generate Ag-specific induced Tregs (iTregs) and tested their efficacy and selectivity in the prevention of GVHD in pre-clinical models of bone marrow transplantation (BMT). We selected HY as a target antigen because it is a naturally processed, ubiquitously expressed minor histocompatibility antigen (miHAg) with a proven role in GVHD and GVL effect. We generated HY-specific iTregs (HY-iTregs) from resting CD4 T cells derived from TCR transgenic mice, in which CD4 cells specifically recognize HY peptide. We found that HY-iTregs were highly effective in preventing GVHD in male (HY+) but not female (HY−) recipients using MHC II-mismatched, parent → F1 and miHAg-mismatched murine BMT models. Interestingly, the expression of target Ag (HY) on the hematopoietic or non- hematopoietic compartment alone was sufficient for iTregs to prevent GVHD. Furthermore, treatment with HY-iTregs still preserved the GVL effect even against pre-established leukemia. We found that HY-iTregs were more stable in male than in female recipients. Furthermore, HY-iTregs expanded extensively in male but not female recipients, which in turn significantly reduced donor effector T-cell (Teff) expansion, activation, and migration into GVHD target organs resulting in effective prevention of GVHD. This study demonstrates that iTregs specific for HY miHAgs are highly effective in controlling GVHD in an Ag-dependent manner while sparing the GVL effect.

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Inhibition of the Alloimmune Response through the Generation of Regulatory T Cells by a MHC Class II-Derived Peptide

Cited by 10 publications

References 45 publications

Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation

Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation

Manipulating IL-2 Availability Amid Presentation of Donor MHC Antigens Suppresses Murine Alloimmune Responses by Inducing Regulatory T Cells

HY-Specific Induced Regulatory T Cells Display High Specificity and Efficacy in the Prevention of Acute Graft-versus-Host Disease

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