CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVL

Matte-Martone, Catherine; Liu, Jinli; Jain, Dhanpat; McNiff, Jennifer M.; Shlomchik, Warren D.

doi:10.1182/blood-2007-11-125294

Cited by 54 publications

(57 citation statements)

References 40 publications

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“…Indeed, CD8 T cells cannot induce GVHD in these systems (48). Although this pathway can effectively induce CD4-dependent cytokine-mediated GVHD (49), the ability of CD8 T cells to mediate GVHD is extremely limited in the absence of effective cognate TCR-MHC interactions (49,50). A recent study of CD8 iTregs used a xenograft system in which human APCs were engrafted prior to secondary transplantation to allow the induction of GVHD by direct presentation of human alloantigens to human T cells (46).…”

Section: Discussionmentioning

confidence: 99%

Induced Regulatory T Cells Promote Tolerance When Stabilized by Rapamycin and IL-2 In Vivo

Zhang

Tey

Koyama

et al. 2013

The Journal of Immunology

107

106

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Natural regulatory T cells (nTregs) play an important role in tolerance; however, the small numbers of cells obtainable potentially limit the feasibility of clinical adoptive transfer. Therefore, we studied the feasibility and efficacy of using murine-induced regulatory T cells (iTregs) for the induction of tolerance after bone marrow transplantation. iTregs could be induced in large numbers from conventional donor CD4 and CD8 T cells within 1 wk and were highly suppressive. During graft-versus-host disease (GVHD), CD4 and CD8 iTregs suppressed the proliferation of effector T cells and the production of proinflammatory cytokines. However, unlike nTregs, both iTreg populations lost Foxp3 expression within 3 wk in vivo, reverted to effector T cells, and exacerbated GVHD. The loss of Foxp3 in iTregs followed homeostatic and/or alloantigen-driven proliferation and was unrelated to GVHD. However, the concurrent administration of rapamycin, with or without IL-2/anti–IL-2 Ab complexes, to the transplant recipients significantly improved Foxp3 stability in CD4 iTregs (and, to a lesser extent, CD8 iTregs), such that they remained detectable 12 wk after transfer. Strikingly, CD4, but not CD8, iTregs could then suppress Teff proliferation and proinflammatory cytokine production and prevent GVHD in an equivalent fashion to nTregs. However, at high numbers and when used as GVHD prophylaxis, Tregs potently suppress graft-versus-leukemia effects and so may be most appropriate as a therapeutic modality to treat GVHD. These data demonstrate that CD4 iTregs can be produced rapidly in large, clinically relevant numbers and, when transferred in the presence of systemic rapamycin and IL-2, induce tolerance in transplant recipients.

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Section: Discussionmentioning

confidence: 99%

Induced Regulatory T Cells Promote Tolerance When Stabilized by Rapamycin and IL-2 In Vivo

Zhang

Tey

Koyama

et al. 2013

The Journal of Immunology

107

106

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“…Thus, the expression of MHC class I on target cells is required for CD8 1 T-cell-dependent GVHD and GVL, whereas MHC class II expression is required for CD4 1 T-celldependent GVL, but not GVHD. 94,95 The latter is due to the fact that inflammatory cytokines produced by CD4…”

Section: Gvhd and The Inhibition Of Antigen Presentationmentioning

confidence: 99%

Alloantigen presentation and graft-versus-host disease: fuel for the fire

Koyama

Hill

2016

Blood

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Allogeneic stem cell transplantation (SCT) is a unique procedure, primarily in patients with hematopoietic malignancies, involving chemoradiotherapy followed by the introduction of donor hematopoietic and immune cells into an inflamed and lymphopenic environment. Interruption of the process by which recipient alloantigen is presented to donor T cells to generate graft-versus-host disease (GVHD) represents an attractive therapeutic strategy to prevent morbidity and mortality after SCT and has been increasingly studied in the last 15 years. However, the immune activation resulting in GVHD has no physiological equivalent in nature; alloantigen is ubiquitous, persists indefinitely, and can be presented by multiple cell types at numerous sites, often on incompatible major histocompatibility complex, and occurs in the context of intense inflammation early after SCT. The recognition that alloantigen presentation is also critical to the development of immunological tolerance via both deletional and regulatory mechanisms further adds to this complexity. Finally, GVHD itself appears capable of inhibiting the presentation of microbiological antigens by donor dendritic cells late after SCT that is mandatory for the establishment of effective pathogen-specific immunity. Here, we review our current understanding of alloantigen, its presentation by various antigen-presenting cells, subsequent recognition by donor T cells, and the potential of therapeutic strategies interrupting this disease-initiating process to modify transplant outcome.

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“…In a delayed T-cell infusion model, Fluttes et al also found alloreactive T-cell responses to be diminished when antigen was widespread. 47 To maximize GVL efficacy and to minimize GVHD, 48 it would be ideal if targeted miHAs were restricted to the hematopoietic system. However, it is difficult to accurately assess miHA distribution, especially as a given gene may only be expressed in a subset of cells or may be induced only under specific conditions, perhaps even by the alloimmune response itself.…”

Section: Memory T Cells From Miha-vaccinated Donors Improve Gvl 5973mentioning

confidence: 99%

Memory T cells from minor histocompatibility antigen–vaccinated and virus-immune donors improve GVL and immune reconstitution

Matte-Martone²,

Zheng³

et al. 2011

Blood

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IntroductionAllogeneic hematopoietic stem cell transplantation (alloSCT) can be a curative therapy for patients with hematologic malignancies. Mature donor T cells in the allograft are critical for reconstituting T-cell immunity in recipients and mediate an alloimmune antileukemia/lymphoma effect called GVL. In MHC-matched alloSCT, alloimmune T cells target minor histocompatibility antigens (miHAs), which are peptide products of polymorphic genes that distinguish hosts from donors. 1 Unfortunately, alloreactive T cells also attack normal host tissues, causing GVHD. A longstanding and elusive goal in the alloSCT field has been to develop approaches that preserve GVL and immune reconstitution while minimizing GVHD. A second challenge has been how to augment GVL to overcome GVL resistance, as cancer relapse is the single greatest cause of death after transplantation. 2 The risk of relapse is not spread evenly across cancer types. Some malignancies, such as chronic-phase chronic myelogenous leukemia (CP-CML), are extremely GVL sensitive, 3 whereas other types of leukemias, such as blast-crisis CML (BC-CML) and acute myelogenous leukemia, are relatively GVL-resistant. 3,4 One approach for improving GVL would be to broadly augment the alloimmune response by reducing the intensity of immunosuppression. However, this increases the risk for serious and lifethreatening GVHD. 5 Another strategy has been to develop T-cell therapies with a single target specificity, such as those that recognize a single miHA, with the idea that such T cells could augment GVL with a reduced risk for inducing GVHD. 1,6 These T cells can be clonal, polyclonal, or genetically modified to express defined antigen receptors. 7,8 Although there are some promising results, 9,10 such approaches have not yet been widely applied. Transferred cells have in general not survived well in vivo, perhaps because they were activated effectors. In addition, these methodologies are labor intensive and require technical expertise and facilities not available at most centers.We reasoned that an alternative to T-cell engineering would be to increase the frequency of allograft T cells that mediate GVL by vaccinating donors against a single miHA. There is evidence that functional T-cell memory against miHAs can be generated in vivo in humans. [11][12][13] GVHD is increased when donors are multiparous, 12 presumably because of priming against fetal miHAs. Blood transfusion of even aplastic anemia patients increases the risk of HLA-matched allograft rejection. 13 If donors could be vaccinated against single miHAs, then the selective transfer of donor memory T cells (T M ) could improve GVL. T M generated in the donor by prior pathogen infection would also be transferred, thereby augmenting immune reconstitution.In the present study, we show that miHA vaccination of donors greatly increases CD8 ϩ T M -mediated GVL against GVL-sensitive mouse CP-CML (mCP-CML) 14 and GVL-resistant mouse BC-CML (mBC-CML) 15 induced by bcr-abl or bcr-abl and NUP98/ HOXA9 fusion cDNAs, respec...

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CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVL

Abstract: Whether T-cell antigen receptors (TCR) on donor T cells require direct interac

Cited by 54 publications

References 40 publications

Induced Regulatory T Cells Promote Tolerance When Stabilized by Rapamycin and IL-2 In Vivo

Induced Regulatory T Cells Promote Tolerance When Stabilized by Rapamycin and IL-2 In Vivo

Alloantigen presentation and graft-versus-host disease: fuel for the fire

Memory T cells from minor histocompatibility antigen–vaccinated and virus-immune donors improve GVL and immune reconstitution

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