Purinergic signalling in graft-versus-host disease

Allogeneic hematopoietic stem cell transplantation (HSCT) is used to treat blood cancers and other blood disorders. In about half of cases, this therapy is used to treat people with acute myeloid leukaemia, with the remaining cases used for the treatment of acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndromes and related malignancies, lymphomas, plasma cell disorders or non-malignant disorders [1]. Allogeneic HSCT involves the transplantation of hematopoietic stem cells (HSCs) from a fully or partially matched healthy donor to a pre-conditioned recipient, with peripheral blood used as the main source of HSCs to reconstitute hematopoiesis [2]. In recipients with a blood cancer, donor leukocytes arising from the donor HSCs, also mediate graft-versus-leukemia (GVL) immunity to prevent disease relapse [3]. However, in up to 70% of recipients, donor leukocytes can also mediate graft-versus-host disease (GVHD), an inflammatory disorder that is the most common cause of non-relapse mortality following allogeneic HSCT [2].

In GVHD, donor leukocytes damage the gastrointestinal tract, liver, skin and lungs, with increasing evidence that the brain, eyes, kidneys, ovaries and testes can also be damaged [4,5]. GVHD can occur in two main forms, acute and chronic GVHD, which are mechanistically distinct as described elsewhere [6]. Briefly, acute GVHD is initiated by the release of inflammatory molecules including damage-associated molecular patterns (DAMPs) from damaged tissues, as a result of the pre-conditioning regime. These molecules then activate host leukocytes to cause further tissue damage and the activation of host and donor antigen presenting cells (APCs). These APCs in turn stimulate allogeneic-reactive donor T cells to differentiate into effector T cells that mediate tissue damage through the release of pro-inflammatory cytokines and other cytotoxic molecules. Chronic GVHD is also initiated by the pre-conditioning regime and ensuing inflammation, which stimulates allogeneic-reactive donor T cells, including T helper follicular, and donor B cells to produce antibodies that can deposit on GVHD tissues promoting damage. Additionally, Fc receptor-bearing monocytes and macrophages can bind the deposited antibodies to stimulate fibroblasts, leading to tissue fibrosis. Central to both acute and chronic GVHD is the loss of regulatory T cells (Tregs), which when present suppress the activation of allogeneic-reactive host T cells and in the case of chronic GVHD, B cell activation, to restrict GVHD development.

Extracellular ATP is released as a result of the pre-conditioning regime in allogeneic HSCT and serves as a DAMP to initiate GVHD, and continues to be released from damaged tissues during disease progression [7]. Extracellular ATP forms part of the purinergic signalling network. This network also includes ATP-gated P2X receptor ion channels (P2X1, P2X2, P2X3, P2X4, P2X5, P2X6 and P2X7), G-protein coupled nucleotide P2Y receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14) and G-protein coupled adenosine receptors (A1, A2A, A2B and A3). Further, this network involves a variety of ecto-nucleotidases including CD39 (ecto-nucleoside triphosphate diphosphohydrolase 1) that converts ATP and ADP to AMP, and CD73 (ecto-5′-nucleotidase) that converts AMP to adenosine [8]. These receptors and ecto-nucleotidases are present on various cell types including leukocytes, where they play important roles in inflammation and inflammatory disorders, with extracellular ATP functioning as a DAMP [9] and as an autocrine signalling molecule of leukocytes [10]. Accumulating evidence, largely from allogeneic and humanised mouse models, has indicated important roles for some of these molecules in GVHD, as extensively reviewed elsewhere [11]. Here, we will outline the current views regarding the roles of purinergic signalling in GVHD including descriptions of more recent observations.

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