The Role of Purine Metabolites as DAMPs in Acute Graft-versus-Host Disease

Apostolova, Petya; Zeiser, Robert

doi:10.3389/fimmu.2016.00439

Cited by 30 publications

(32 citation statements)

References 89 publications

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“…It has been reported that ATP regulates the function of lymphoid cells with opposite effects depending on the cellular subsets analyzed ( 11 , 46 , 47 ). In case of Tregs, ATP may directly elicit their suppressive function or may be metabolized by ecto-5′-nucleotidases, such as CD39 and CD73, into adenosine, which enhances Tregs activity ( 11 – 13 ).…”

Section: Discussionmentioning

confidence: 99%

ATP Release from Chemotherapy-Treated Dying Leukemia Cells Elicits an Immune Suppressive Effect by Increasing Regulatory T Cells and Tolerogenic Dendritic Cells

et al. 2017

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Chemotherapy-induced immunogenic cell death can favor dendritic cell (DC) cross-priming of tumor-associated antigens for T cell activation thanks to the release of damage-associated molecular patterns, including ATP. Here, we tested the hypothesis that in acute myeloid leukemia (AML), ATP release, along with its well-known immune stimulatory effect, may also contribute to the generation of an immune suppressive microenvironment. In a cohort of AML patients, undergoing combined daunorubicin and cytarabine chemotherapy, a population of T regulatory cells (Tregs) with suppressive phenotype, expressing the immune checkpoint programmed cell death protein 1 (PD-1), was significantly increased. Moving from these results, initial in vitro data showed that daunorubicin was more effective than cytarabine in modulating DC function toward Tregs induction and such difference was correlated with the higher capacity of daunorubicin to induce ATP release from treated AML cells. DCs cultured with daunorubicin-treated AML cells upregulated indoleamine 2,3-dioxygenase 1 (IDO1), which induced anti-leukemia Tregs. These data were confirmed in vivo as daunorubicin-treated mice show an increase in extracellular ATP levels with increased number of Tregs, expressing PD-1 and IDO1+CD39+ DCs. Notably, daunorubicin failed to induce Tregs and tolerogenic DCs in mice lacking the ATP receptor P2X7. Our data indicate that ATP release from chemotherapy-treated dying cells contributes to create an immune suppressive microenvironment in AML.

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Section: Discussionmentioning

confidence: 99%

ATP Release from Chemotherapy-Treated Dying Leukemia Cells Elicits an Immune Suppressive Effect by Increasing Regulatory T Cells and Tolerogenic Dendritic Cells

et al. 2017

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“…An important inducer of the Nlrp3 inflammasome in GvHD is activation of purinergic signaling by eATP [111][112][113]. After binding to the purinergic receptors P2X7 and P2X4, eATP induces activation of the Nlrp3 inflammasome [111].…”

Section: The Nlrp3 Inflammasome In Gvhdmentioning

confidence: 99%

The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

et al. 2020

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Recent investigations indicate that hematopoiesis is coregulated by innate immunity signals and by pathways characteristic of the activation of innate immunity cells that also operate in normal hematopoietic stem progenitor cells (HSPCs). This should not be surprising because of the common developmental origin of these cells from a hemato/lymphopoietic stem cell. An important integrating factor is the Nlrp3 inflammasome, which has emerged as a major sensor of changes in body microenvironments, cell activation, and cell metabolic activity. It is currently the best-studied member of the inflammasome family expressed in hematopoietic and lymphopoietic cells, including also HSPCs. It is proposed as playing a role in (i) the development and expansion of HSPCs, (ii) their release from bone marrow (BM) into peripheral blood (PB) in stress situations and during pharmacological mobilization, (iii) their homing to BM after transplantation, and (iv) their aging and the regulation of hematopoietic cell metabolism. The Nlrp3 inflammasome is also involved in certain hematological pathologies, including (i) myelodysplastic syndrome, (ii) myeloproliferative neoplasms, (iii) leukemia, and (iv) graft-versus-host disease (GvHD) after transplantation. The aim of this review is to shed more light on this intriguing intracellular protein complex that has become a "rising star" in studies focused on both normal steady-state and pathological hematopoiesis.

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“…In addition, numerous inflammatory markers (such as erythrocyte sedimentation rate and C-reactive protein (CRP) levels), angiogenic markers (such as follistatin and angiopoietin 2) and microbiota-derived metabolites (such as butyrate) are under active investigation as biomarkers; however, these markers are non-specific to gastrointestinal acute GVHD 54–56 . In small studies, faecal calprotectin levels were demonstrated to have potential as a diagnostic tool 57,58 .…”

Section: Diagnosismentioning

confidence: 99%

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

Naymagon

Wong

et al. 2017

Nat Rev Gastroenterol Hepatol

113

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Haematopoietic stem cell transplantation (HSCT) is central to the management of many haematological disorders. A frequent complication of HSCT is acute graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack healthy recipient tissues. The gastrointestinal system is among the most common sites affected by acute GVHD, and severe manifestations of acute GVHD of the gut portends a poor prognosis in patients after HSCT. Acute GVHD of the gastrointestinal tract presents both diagnostic and therapeutic challenges. Although the clinical manifestations are nonspecific and overlap with those of infection and drug toxicity, diagnosis is ultimately based on clinical criteria. As reliable serum biomarkers have not yet been validated outside of clinical trials, endoscopic and histopathological evaluation continue to be utilized in diagnosis. Once a diagnosis of gastrointestinal acute GVHD is established, therapy with systemic corticosteroids is typically initiated, and non-responders can be treated with a wide range of second-line therapies. In addition to treating the underlying disease, the management of complications including profuse diarrhoea, severe malnutrition and gastrointestinal bleeding is paramount. In this Review, we discuss strategies for the diagnosis and management of acute GVHD of the gastrointestinal tract as they pertain to the practising gastroenterologist.

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The Role of Purine Metabolites as DAMPs in Acute Graft-versus-Host Disease

Cited by 30 publications

References 89 publications

ATP Release from Chemotherapy-Treated Dying Leukemia Cells Elicits an Immune Suppressive Effect by Increasing Regulatory T Cells and Tolerogenic Dendritic Cells

ATP Release from Chemotherapy-Treated Dying Leukemia Cells Elicits an Immune Suppressive Effect by Increasing Regulatory T Cells and Tolerogenic Dendritic Cells

The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

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