Human CD39 overexpression or APT102 recombinant apyrase administration enhances Treg and Tr1 cell immunity in inflammatory bowel disease

Abstract CD39/ENTPD1 is an ectonucleotidase that scavenges pro-inflammatory nucleotides to ultimately generate adenosine. Single nucleotide polymorphisms within the promoter region of the ENTPD1 gene are linked to higher rates of inflammatory bowel disease (IBD) in humans. Furthermore, decreased levels of CD39 expression are noted in Th17 cells purified from patients with Crohn’s disease, because of aberrant signaling by aryl-hydrocarbon-receptor (AhR) in response to endogenous ligands e.g. unconjugated bilirubin (UCB). Deletion of CD39 increases susceptibility to disease in experimental colitis while overexpression of human CD39 (hCD39) in transgenic mice results in protection from ischemia reperfusion injury and thromboembolism. Here, we show that overexpression of hCD39 results in amelioration of dextran-sulfate-sodium (DSS)-induced experimental colitis and protects mice from the deleterious effects of systemic hypoxia, pharmacologically induced by deferoxamine. We further report that treatment with APT102, soluble recombinant apyrase, boosts Foxp3 expression in wild type Treg and renders Crohn’s-derived Treg and Tr1 cells more responsive to UCB-AhR stimulation in vitro. Further, APT102 enhances the beneficial regulatory effects of UCB in DSS colitic mice, in vivo. We conclude that transgenic overexpression of hCD39 is beneficial in experimental colitis and ameliorates systemic hypoxic injury in vivo. Exogenous administration of APT102 promotes AhR-mediated regulatory effects in vivo while boosting the regulatory T-cell pool in Crohn’s disease ex vivo. Boosting endogenous CD39 or augmenting ectonucleotidase activity, as with pharmacological treatment with APT102, might represent therapeutic options in IBD.