title: Adenosine A2A receptor antagonists: blockade of adenosinergic effects and T regulatory cells.
abstract: The intensity and duration of host responses are determined by protective mechanisms that control tissue injury by dampening down inflammation. Adenosine generation and consequent effects, mediated via A2A adenosine receptors (A2AR) on effector cells, play a critical role in the pathophysiological modulation of these responses in vivo. Adenosine is both released by hypoxic cells/tissues and is also generated from extracellular nucleotides by ecto-enzymes e.g. CD39 (ENTPD1) and CD73 that are expressed by the vasculature and immune cells, in particular by T regulatory cell. In general, these adenosinergic mechanisms minimize the extent of collateral damage to host tissues during the course of inflammatory reactions. However, induction of suppressive pathways might also cause escape of pathogens and permit dissemination. In addition, adenosinergic responses may inhibit immune responses while enhancing vascular angiogenic responses to malignant cells that promote tumor growth. Novel drugs that block A2AR-adenosinergic effects and/or adenosine generation have the potential to boost pathogen destruction and to selectively destroy malignant tissues. In the latter instance, future treatment modalities might include novel 'anti-adenosinergic' approaches that augment immune clearance of malignant cells and block permissive angiogenesis. This review addresses several possible pharmacological modalities to block adenosinergic pathways and speculates on their future application together with impacts on human disease.
authors.affiliation: New England Inflammation and Tissue Protection Institute, Consortium at Northeastern University, 113 Mugar Building, 360 Huntington Avenue, Boston, MA 02115, USA. m.sitkovsky@neu.edu
authors.forename: M
authors.initials: M
authors.lastname: Sitkovsky
authors.forename: D
authors.initials: D
authors.lastname: Lukashev
authors.forename: S
authors.initials: S
authors.lastname: Deaglio
authors.forename: K
authors.initials: K
authors.lastname: Dwyer
authors.forename: S C
authors.initials: SC
authors.lastname: Robson
authors.forename: A
authors.initials: A
authors.lastname: Ohta
mesh_terms: D000241:Adenosine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D043562:Receptors, G-Protein-Coupled; D000241:Adenosine