Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation

Lappas, Courtney M.; Liu, Po-Ching; Linden, Joel; Kang, Elizabeth M.; Malech, Harry L.

doi:10.1189/jlb.0609388

Cited by 43 publications

(54 citation statements)

References 43 publications

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“…Furthermore, CD73-generated adenosine is known to inhibit proinflammatory cytokine production, 28 to decrease the expression of adhesion molecules on endothelial cells, 49 and to inhibit endothelial permeability, 7 actions that should reduce the severity of GVHD. Our findings extend the observations of Lappas et al 13 who showed that pharmacologic activation of the A 2A AR can reduce the severity of GVHD. In contrast, our results showed that endogenous levels of A 2A AR signaling reduced the expansion of allogeneic T cells and demonstrated that CD73 was the source of a significant portion of the activating ligand.…”

Section: Discussionsupporting

confidence: 92%

“…14 Another A 2A AR agonist was shown to attenuate acute GVHD after allo-HCT. 13 These findings support the concept that extracellular adenosine counteracts ATPtriggered immune activation as a negative feedback mechanism to prevent uncontrolled tissue destruction because of excessive inflammation.…”

Section: Introductionsupporting

confidence: 69%

“…[10][11][12] In most circumstances, A 1 and A 3 receptor triggering is proinflammatory, whereas activation of A 2A and A 2B receptors is antiinflammatory or tolerogenic. 13,14 The importance of CD73 in producing adenosine for AR signaling has been revealed through studies with CD73-deficient mice. For example, CD73-generated adenosine reduces inflammation and fibrosis in lungs of bleomycin-treated mice 15 and is tolerogenic for cardiac and airway allografts.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of CD73/ecto-5′-nucleotidase in mice enhances acute graft-versus-host disease

Tsukamoto

Chernogorova

Ayata

et al. 2012

Blood

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Extracellular ATP and adenosine have immunoregulatory roles during inflammation. Elevated extracellular ATP is known to exacerbate GVHD, and the pharmacologic activation of the adenosine A 2A receptor is protective. However, the role of endogenous adenosine is unknown. We used gene-targeted mice and a pharmacologic inhibitor to test the role of adenosine generated by CD73/ecto-5-nucleotidase in GVHD. In allogeneic transplants, both donor and recipient CD73 were protective, with recipient CD73 playing the dominant role. CD73 deficiency led to enhanced T-cell expansion and IFN-␥ and IL-6 production, and the migratory capacity of Cd73 ؊/؊ T cells in vitro was increased. However, the number of regulatory T cells and expression of costimulatory molecules on antigen-presenting cells were unchanged. A 2A receptor deficiency led to increased numbers of allogeneic T cells, suggesting that signaling through the A 2A receptor via CD73-generated adenosine is a significant part of the mechanism by which CD73 limits the severity of GVHD. IntroductionPatients with hematologic malignancies that are refractory to conventional chemotherapy have a chance of cure by allogeneic hematopoietic stem cell transplantation (allo-HCT). 1 However, the success of this treatment is limited by GVHD. 2 We have recently shown that extracellular ATP, which is released from dying or stressed cells and serves as an endogenous danger signal to evoke systemic inflammatory responses, enhances GVHD by activation of the purinergic receptor P2X 7 R. 3,4 The abundance of extracellular ATP is regulated by ecto-nucleotidases, such as CD39, which dephosphorylates ATP to ADP and AMP. Extracellular AMP is dephosphorylated to adenosine via the action of CD73, a glycosyl phosphatidylinositol-anchored glycoprotein with ecto-5Ј-nucleotidase enzyme activity. 5-7 CD73 is expressed on many cell types, including subsets of T lymphocytes, endothelial cells, and epithelial cells. 7,8 It is also present as a secreted form lacking a glycosyl phosphatidylinositol anchor. 9 CD73-generated adenosine can activate any of 4 G-protein-coupled 7-transmembrane-spanning adenosine receptors (ARs; A 1 , A 2A , A 2B and A 3 ) and can act as either a pro-or anti-inflammatory mediator depending on the physiologic setting and the type of AR engaged. [10][11][12] In most circumstances, A 1 and A 3 receptor triggering is proinflammatory, whereas activation of A 2A and A 2B receptors is antiinflammatory or tolerogenic. 13,14 The importance of CD73 in producing adenosine for AR signaling has been revealed through studies with CD73-deficient mice. For example, CD73-generated adenosine reduces inflammation and fibrosis in lungs of bleomycin-treated mice 15 and is tolerogenic for cardiac and airway allografts. 16,17 CD73-dependent A 2B AR signaling protects mice during renal ischemia, 18 inhibits systemic vascular leakage during hypoxia, 19,20 and is also required for cardioprotection as a result of ischemic preconditioning. 21 Extracellular adenosine inhibits platelet activation and leukocyte...

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Section: Discussionsupporting

confidence: 92%

Section: Introductionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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Deficiency of CD73/ecto-5′-nucleotidase in mice enhances acute graft-versus-host disease

Tsukamoto

Chernogorova

Ayata

et al. 2012

Blood

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“…29,83,84 The protective role of adenosine signaling via the Adora2a in GVHD is also supported by studies demonstrating that treatment of animals with the selective Adora2a agonist ATL146e reduces cardinal features of GVHD by enhancing the number of donor-derived Tregs. 85,86 In summary, these studies indicate that ATP signaling through the P2X 7 R is associated with enhanced generation of allogeneic donor T cells and suppression of Tregs, thereby contributing to the development of GVHD. In contrast, CD73-dependent adenosine generation and signaling through the Adora2a dampens GVHD via inhibition of allogeneic T cells and promotion of donor Tregs.…”

Section: Graft-versus-host Diseasementioning

confidence: 80%

Extracellular nucleotide and nucleoside signaling in vascular and blood disease

Idzko

Ferrari

Riegel

et al. 2014

Blood

122

106

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Nucleotides and nucleosides—such as adenosine triphosphate (ATP) and adenosine—are famous for their intracellular roles as building blocks for the genetic code or cellular energy currencies. In contrast, their function in the extracellular space is different. Here, they are primarily known as signaling molecules via activation of purinergic receptors, classified as P1 receptors for adenosine or P2 receptors for ATP. Because extracellular ATP is rapidly converted to adenosine by ectonucleotidase, nucleotide-phosphohydrolysis is important for controlling the balance between P2 and P1 signaling. Gene-targeted mice for P1, P2 receptors, or ectonucleotidase exhibit only very mild phenotypic manifestations at baseline. However, they demonstrate alterations in disease susceptibilities when exposed to a variety of vascular or blood diseases. Examples of phenotypic manifestations include vascular barrier dysfunction, graft-vs-host disease, platelet activation, ischemia, and reperfusion injury or sickle cell disease. Many of these studies highlight that purinergic signaling events can be targeted therapeutically.

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“…Activated Tcons proliferate and trigger release of alarmins, such as IL-33 and its soluble receptor ST2, from non-HP APCs, such as stromal cells and endothelium; these activated Tcons also express the integrin receptor α 4 β 7 , which directs their migration back to intestinal tissue after entering the villus capillaries. the absence of CD73 on either donor T cells or host APCs exacerbated GVHD (54)(55)(56). UA, a purine metabolite released from damaged cells, is an endogenous DAMP that stimulates DCs and activates CD8 + T cell cytotoxic functions (45,57).…”

Section: Immune Homeostasis In the Gi Tractmentioning

confidence: 99%

Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis

Ferrara¹,

Smith²,

Sheets³

et al. 2017

Journal of Clinical Investigation

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Acute graft-versus-host disease (aGVHD) was noted as a complication of allogeneic bone marrow (BM) transplantation in animal models more than six decades ago (1, 2). The initial descriptions of aGVHD differentiated it from the complications of BM aplasia and focused on the severe consequences of GVHD for lower gastrointestinal (GI) tract function, as manifested by weight loss and profound diarrhea. Subsequent studies clearly identified donor T cells as the critical cells required for the induction of aGVHD (3)(4)(5). aGVHD was shown to predominantly involve the skin, liver, and lower GI tract and, later, the upper GI tract (6). In the absence of approaches to prevent aGVHD, this complication occurs in close to 100% of recipients of allogeneic BM/stem cell transplants (allogeneic hematopoietic cell transplantation, allo-HCT), greatly limiting the survival of the first cohort of patients who underwent allo-HCT. Lower GI tract GVHD: clinical findingsDespite the use of prophylaxis to prevent aGVHD, without rigorous T cell depletion this complication occurs in 30%-70% of patients undergoing allo-HCT (7-9). Standard treatment of aGVHD is the administration of systemic corticosteroids and additional immunosuppressive agents, which, as primary therapy, do not substantially improve patient outcomes (10). Thirty to seventyfive percent of patients who develop aGVHD will have a complete response to corticosteroid therapy (11).The outcome for patients with severe aGVHD (grades III-IV) of the lower GI tract is poor, with 25% overall survival (12). Four risk factors (corticosteroid resistance, age under 18 years at time of transplant, GI tract bleeding, and total bilirubin greater than 3 mg/dl) were found on multivariate analysis to be statistically associated with poor survival; no patients with all 4 factors survived, highlighting the critical need to improve survival for these patients. This Review will focus on recent findings regarding the homeostatic mechanisms of the lower GI tract that relate to the pathophysiology of aGVHD involving the distal small intestine and colon. Immune homeostasis in the GI tractThe immune balance of the human small intestine and colon is complex. There are over 100 trillion bacteria that are critical to the function of the GI tract, and individuals are exposed to a huge number of food-borne antigens on a daily basis. Thus, there must exist dynamic and robust mechanisms that mediate immune responses to pathogenic organisms but that prevent immune responses to normal flora and dietary antigens.Antigen-presenting cells in the GI tract. Specialized hematopoietic antigen-presenting cells (APCs) in the GI tract include multiple subpopulations of dendritic cells (DCs) and macrophages ( Figure 1). DCs in the lamina propria (LP) and Peyer's patch sample luminal antigens and migrate to regional lymph nodes (LNs) to activate immune responses (13,14). Macrophages are sessile and are the most abundant innate immune cells in the intestine; they maintain homeostasis by phagocytosing microorganisms and apop...

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Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation

Cited by 43 publications

References 43 publications

Deficiency of CD73/ecto-5′-nucleotidase in mice enhances acute graft-versus-host disease

Deficiency of CD73/ecto-5′-nucleotidase in mice enhances acute graft-versus-host disease

Extracellular nucleotide and nucleoside signaling in vascular and blood disease

Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis

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