Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice

Wikström, Matthew E.; Fleming, Peter; Kuns, Rachel D.; Schuster, Iona S.; Voigt, Valentina; Miller, Gregory; Clouston, Andrew D.; Tey, Siok-Keen; Andoniou, Christopher E.; Hill, Geoffrey R.; Degli-Esposti, Mariapia A.

doi:10.1182/blood-2015-01-622837

Cited by 24 publications

(22 citation statements)

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“…28 Furthermore, in the presence of GVHD, CMV predisposes to induce a striking cytopathy resulting in universal mortality. 29 Disappointing outcomes have also been reported in several small retrospective trials of therapy targeting both IL-2 and TNF in SR-aGVHD. 30,31 Rager et al retrospectively reviewed their experience using combination anti-cytokine therapy of daclizumab and infliximab in a cohort that included 17 patients with SR-aGVHD.…”

Section: Discussionmentioning

confidence: 99%

Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: A multi-center prospective study

Tan

Xiao

et al. 2017

OncoImmunology

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Acute graft versus host disease (aGVHD) remains a major problem after allogeneic hematopoietic stem cell transplantation. Standard frontline therapy for aGVHD involves corticosteroids. However, fewer than half of patients have a lasting complete response. The long-term mortality rate of steroid-refractory aGVHD (SR-aGVHD) remains around 70%. To date, no consensus has been reached regarding the optimal salvage treatment for SR-aGVHD. We performed the first prospective, multi-center clinical trial to assess the efficacy and safety of a novel approach to treat severe (grades III-IV) SR-aGVHD with the combination of basiliximab and etanercept. Sixty-five patients with severe SR-aGVHD from six centers were included. The median number of basiliximab infusions was 4 (range 2-11) and of etanercept was 9 (range 2-12). At day 28 after starting the combination treatment, overall response (complete and partial response: CRCPR) to second-line treatment was 90.8% with 75.4% being CR. The incidences of CR per organ were 100%, 73.8%, and 79.7% for skin, liver, and gut involvement, respectively. Patients >30-y old (p D 0.043, RR D 3.169), development of grades III-IV liver aGVHD (p D 0.007, RR D 5.034) and cytomegalovirus (CMV) reactivation (p D 0.035, RR D 4.02) were independent predictors for incomplete response. Combined treatment with basiliximab and etanercept resulted in improved CR to visceral aGVHD and significantly superior 2-y overall survival (54.7% vs. 14.8%, p <0.001) compared with classical salvage treatments. Our data suggest that the combination of basiliximab and etanercept may constitute a promising new treatment option for SR-aGVHD.

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Section: Discussionmentioning

confidence: 99%

Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: A multi-center prospective study

Tan

Xiao

et al. 2017

OncoImmunology

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“…88 Subsequent work demonstrates this results in overwhelming cytomegalovirus (CMV) disease with hepatic necrosis and lethality due to the inability to generate pathogen-specific immunity. 89 Conversely, CMV reactivation may be correlated with reduced relapse of acute myeloid leukemia. 90 Although CMV is detected in leukemic blasts 91 and this is speculated to provide virus-derived antigens as GVL targets, the mechanisms involved will need further careful experimentation.…”

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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“…The severity of GVHD was assessed by weight loss in the host mice [12, 13]. A weight loss of more than 10% indicated the occurrence of GVHD.…”

Section: Methodsmentioning

confidence: 99%

Activation of the Nuclear Erythroid 2-Related Factor 2 Antioxidant Responsive Element (Nrf2-ARE) Signaling Pathway Alleviates Acute Graft-Versus-Host Disease by Reducing Oxidative Stress and Inhibiting Infiltration of Inflammatory Cells in an Allogeneic Stem Cell Transplantation Mouse Model

Wang

et al. 2018

Med Sci Monit

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BackgroundAcute graft-versus-host disease (aGVHD) limits the wider application of hematopoietic stem cell transplantation (HSCT). We explored the relationship between the Nrf2-ARE signaling pathway and aGVHD and identified effective and efficient therapeutic targets for the prevention and management of aGVHD following HSCT.Material/MethodsC57BL/6 and BALB/c mice were used to establish the aGVHD model. The bone marrow and spleen mononuclear cells were separated from the donor mice and injected into the caudal vein of recipient mice that had undergone total body irradiation (TBI, 8 Gy). Sulforaphane (SFN) was used to activate the Nrf2-ARE signaling pathway.ResultsThe long-term survival rate of the SFN group was higher than that of the control group (40% vs. 0%, p<0.05, n=10). There were worse pathological changes and a greater infiltration of inflammatory cells in the liver, small intestine, and lung tissues of the control group. Furthermore, the Nrf2, NQO1, and HO-1 mRNA and protein levels were higher in the small intestines of the SFN group than in the control group (p<0.05, n=4).ConclusionsThe Nrf2-ARE signaling pathway plays a vital role in preventing aGVHD in an HSCT mouse model by regulating the expression of the downstream antioxidant genes NQO1 and HO-1 and by inhibiting the local inflammatory reaction.

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Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice

Abstract: Key Points GVHD elicits profound defects in DCs that prevent the priming of virus-specific T cells. Transfer of polyclonal T cells from immune donors at transplant provides effective antiviral immunity despite the presence of active GVHD.

Cited by 24 publications

References 44 publications

Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: A multi-center prospective study

Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: A multi-center prospective study

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

Activation of the Nuclear Erythroid 2-Related Factor 2 Antioxidant Responsive Element (Nrf2-ARE) Signaling Pathway Alleviates Acute Graft-Versus-Host Disease by Reducing Oxidative Stress and Inhibiting Infiltration of Inflammatory Cells in an Allogeneic Stem Cell Transplantation Mouse Model

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