Modulation of CD39 and exogenous APT102 correct immune dysfunction in experimental colitis and Crohn’s disease.
J Crohns Colitis. 2019 Nov 06;:
Authors: Robles RJ, Mukherjee S, Vuerich M, Xie A, Harshe R, Cowan PJ, Csizmadia E, Wu Y, Moss AC, Chen R, Robson SC, Longhi MS
BACKGROUND AND AIMS: CD39/ENTPD1 scavenges pro-inflammatory nucleotides, to ultimately generate immunosuppressive adenosine, having a central role in immune-homeostasis. Global deletion of Cd39 increases susceptibility to experimental colitis while single-nucleotide-polymorphisms within the human CD39 promoter, and aberrant patterns of expression during experimental hypoxia, predispose to Crohn’s disease. We aimed to define the impact of transgenic-human-CD39 (hTG) overexpression in experimental colitis and to model therapeutic effects using the recombinant apyrase APT102 in vivo. We also determined in vitro effects of APT102 on phenotypic and functional properties of regulatory T-lymphocytes derived from patients with Crohn’s disease.
METHODS: Colitis was induced upon administration of dextran-sulfate-sodium in wild-type (WT) or hTG mice; and, in another model, by adoptive transfer of CD45RBhigh-cells with or without WT or hTG-Treg. In additional experiments, mice were treated with APT102. Effects of APT102 on phenotype and function of Treg and type-1-regulatory-T (Tr1)-cells were also evaluated, after purification from peripheral blood and lamina propria of Crohn’s patients (n=38).
RESULTS: Overexpression of human CD39 attenuated experimental colitis and protected from deleterious effects of systemic hypoxia, pharmacologically induced by deferoxamine. Administration of APT102 in vivo enhanced the beneficial effects of endogenous Cd39 boosted by the administration of the aryl-hydrocarbon-receptor (AhR) ligand unconjugated bilirubin (UCB). Importantly, supplemental APT102 restored responsiveness to AhR stimulation by UCB in Treg and Tr1-cells, obtained from Crohn’s patients.
CONCLUSIONS: hCD39 overexpression ameliorated experimental colitis and prevented hypoxia-related damage in vivo. Exogenous administration of APT102 boosted AhR-mediated regulatory effects in vivo while enhancing Treg functions in Crohn’s disease in vitro.
PMID: 31693091 [PubMed – as supplied by publisher]