Abstract
Adenosine triphosphate (ATP) is released into the extracellular environment during transplantation, and acts via purinergic receptors to amplify the alloimmune response. Here, using a well-established murine model of allogeneic corneal transplantation, we investigated the immunomodulatory mechanisms of the purinergic receptor antagonist oxidized ATP (oATP). Corneal transplantation was performed using C57BL/6 donors and BALB/c hosts. oATP or sterile saline was administered via intraperitoneal injection for 2 weeks postoperatively. Frequencies of CD45+ leukocytes, CD11b+MHCII+ antigen presenting cells (APCs), CD4+IFN-γ+ effector Th1 cells and CD4+Foxp3+ regulatory T cells (Tregs) were evaluated by flow cytometry. Slit-lamp microscopy was performed weekly for 8 weeks to evaluate graft opacity and determine transplant rejection. Treatment with oATP was shown to significantly reduce graft infiltration of CD45+ leukocytes, decrease APC maturation and suppress effector Th1 cell generation relative to saline-treated control. No difference in Treg frequencies or Foxp3 expression was observed between the oATP-treated and control groups. Finally, oATP treatment was shown to reduce graft opacity and increase graft survival. This report demonstrates that oATP limits the alloimmune response by regulating APC maturation and suppressing the generation of alloreactive Th1 immunity.
Highlights
Keratoplasty is the most common form of allogeneic transplantation worldwide[1], and remains the definitive treatment for many end-stage corneal diseases[2]
Flow cytometric data demonstrated an increase in corneal infiltration of CD45+ leukocytes in saline-treated animals, which was substantially reduced in the oATPtreated group (Fig. 1B)
The frequencies of major histocompatibility complex class II (MHCII)+CD11b+ mature antigen-presenting cells (APCs) were significantly reduced in the oxidized ATP (oATP)-treated group following transplantation, as compared to the saline-treated group (Fig. 1C)
Summary
Keratoplasty is the most common form of allogeneic transplantation worldwide[1], and remains the definitive treatment for many end-stage corneal diseases[2]. There is upregulated local expression of proinflammatory cytokines, chemokines and adhesion molecules[8] This inflammatory milieu triggers the activation of resident and infiltrating host antigen-presenting cells (APCs), which acquire high levels of major histocompatibility complex class II (MHCII) and other costimulatory molecules[9,10]. Various events during allotransplantation promote the release of ATP into the extracellular environment, including perioperative trauma, tissue ischemia/reperfusion and immune cell activation[17]. Previous studies have investigated the blockade of ATP using periodate-oxidized ATP (oATP) as a strategy to promote allograft survival in murine models of heart, lung and islet transplantation[20,21,22]. Our data demonstrate that treatment with oATP suppresses APC maturation, limits CD4+ effector T cell generation and graft infiltration, and increases corneal allograft survival
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