“Many of adenosine's anti- inflammatory effects on human Immune systems
may be due in part to inhibiting NKT cells.” – Joel Linden, Ph.D.
Joel Linden, Ph.D. is a Professor in the Division of Inflammation Biology and a leading expert on adenosine receptors, which are important for regulating inflammation.
Linden received a B.S. from Brown University in Applied Mathematics and Biology and a Ph.D. from the University of Virginia in Pharmacology.
Linden has devoted the past 25 years to the study of the pharmacology, physiology and molecular biology of adenosine receptors and has co-authored over 120 papers and 15 book chapters on this subject. Dr. Linden is the former Chairman of the Research Committee of the Mid-Atlantic Affiliate of the American Heart Association, has served as a member of numerous NIH study sections, received the inventor of the year award from the University of Virginia, and started a successful biopharmaceutical company, Adenosine Therapeutics.
Joel Linden, Ph.D. and his team are focused on the study of adenosine receptors-proteins on the surface of cells that recognize adenosine and related compounds. Adenosine production by cells is increased when cellular energy utilization and the breakdown of adenosine tri-phosphate (ATP) is increased. Hence, adenosine levels are raised when a cell is stressed, activated, or when there is not enough oxygen in the cells, such is the case in ischemic heart disease and sickle cell disease.
Linden is interested in adenosine's affect on disease processes. He found that the adenosine receptor is a very powerful negative regulator of many cells of the immune system including, neutrophils, macrophages and T cells. This is important to disease because by activating adenosine receptors, inflammatory processes can be inhibited. Inflammation has been recognized to play an important role in many diseases, and this discovery opens up numerous new potential treatments for heart failure, diabetes, Crohn's disease, and sickle cell disease-many of which are associated with a low-grade, chronic inflammatory responses.
Linden found that many of the anti-inflammatory effects of adenosine are actually due to their effects on natural killer t-cells (NKT), which regulate a variety of immune responses, including the immune response to tumors and certain infectious agents. For example, NKT cells are involved in ischemia reperfusion injury, which is a type of inflammation and tissue damage that occurs when you either transplant a tissue, have a heart attack, or in the presence of microvascular ischemic episodes which are common in sickle cell disease. The damage caused by the immune system response in these cases is inhibited by adenosine. Tumors evade immune surveillance in part by generating large amouts of adenosine. This suggests that adenosine receptor blockers can be used to enhance the effectiveness of tumor vaccines.
"We think that activating adenosine receptors has great potential to inhibit a wide-range of inflammatory and chronic diseases including arthritis, heart failure, atherosclerosis, type 2 diabetes and sickle cell anemia," said Linden. "A person suffering from sickle cell anemia can go into sudden stress-induced crisis, which causes severe pain. Our research shows that adenosine can be used to block these painful and destructive disease flare-ups. This is a new approach."
Pharmacology of Purine and Pyridine Receptors. Advances in Pharmacology. 2011
International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev. 2011
Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans. Diabetes. 2011
Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease. Blood. 2010
NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-gamma and CXCR3 chemokines. Blood. 2009
Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation. J Leukoc Biol. 2009
The role of adenosine A2A receptor signaling in bronchiolitis obliterans.
Ann Thorac Surg. 2009
Adenosine A2B receptors are highly expressed on murine type II alveolar epithelial cells.
Am J Physiol Lung Cell Mol Physiol. 2009
NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-gamma and CXCR3 chemokines. Blood. 2009
The A2B adenosine receptor impairs the maturation and immunogenicity of dendritic cells.
J Immunol. 2009
CD73 is expressed by human regulatory T helper cells and suppresses proinflammatory cytokine production and Helicobacter felis-induced gastritis in mice. J Infect Dis. 2009
A2A adenosine receptor (AR) activation inhibits pro-inflammatory cytokine production by human CD4+ helper T cells and regulates Helicobacter-induced gastritis and bacterial persistence. Mucosal Immunol. 2009
Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int. 2009
Timing of adenosine 2A receptor stimulation relative to reperfusion has differential effects on infarct size and cardiac function as assessed in mice by MRI. Am J Physiol Heart Circ Physiol. 2008
Adenosine A2A receptor activation reduces infarct size in the isolated, perfused mouse heart by inhibiting resident cardiac mast cell degranulation. Am J Physiol Heart Circ Physiol. 2008
Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov. 2008
Adenosine A2A receptor activation reduces hepatic ischemia reperfusion
injury by inhibiting CD1d-dependent NKT cell activation. J Exp Med. 2006
Myocardial infarct-sparing effect of adenosine A2A receptor activation
is due to its action on CD4+ T lymphocytes. Circulation. 2006
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