The Role of iNKT Cells and Adenosine A2a Receptor Activation in the Pathogenesis of Pulmonary Dysfunction in Sickle Cell Disease

Wallace, Kori L., Department of Microbiology, University of Virginia
Linden, Joel, Department of Microbiology, University of Virginia
Bender, Timothy, Department of Microbiology, University of Virginia
Mcduffie, Marcia, Department of Microbiology, University of Virginia

In sickle cell disease (SCD), misshapen erythrocytes evoke repeated transient bouts of microvascular occlusion that is believed to lead to end-organ damage. Although the sickled red blood cell is the inciting factor in the pathogensis of SCD, the exact mechanism of vaso-occlusion is unknown. Interactions between white blood cells, platelets, and vascular endothelial cells are also believed to contribute to vaso-occlusion is sickle cell disease. Vaso-occlusion leads to downstream tissue ischemia, that eventually resolves and reperfusion to the tissue returns. It is known that ischemiareperfusion injury triggers an inflammatory cascade that is initiated by the activation of CD1d-restricted iNKT cells and can be inhibited by anti-CD1d or adenosine A 2A receptor (A 2A R) agonist treatment. iNKT cells are known to release copious amounts of cytokines when activated, including IFN-γ. Compared to controls (C57BL/6), SCD mice (NY1DD) have more numerous and activated pulmonary iNKT cells and increased pulmonary levels of IFN-γ. IFN-γ is known to recruit effector lymphocytes to areas of inflammation via the IFN-γ inducible chemokine – CXCR3 axis. NY1DD mice were found to have increased levels of IFN-γ inducible chemokines and elevated numbers of lymphocytes expressing the chemokine receptor CXCR3. Strikingly, treating NY1DD mice with anti-CD1d antibody to inhibit iNKT cell activation for only two days reverses baseline pulmonary dysfunction. Anti-CD1d antibodies decrease pulmonary levels of IFN--γ and CXCR3 chemokines. Crossing NY1DD to lymphocyte-deficient Rag1 -/- mice decreases pulmonary dysfunction. This is reversed by the adoptive transfer of 1 million NKT cells. Similar to mice, humans with ii SCD have increased numbers of activated circulating iNKT cells expressing CXCR3. Another method for inhibiting iNKT cells is treatment with adenosine A 2A receptor (A 2A R) agonists. Treating NY1DD mice a selective A 2A R agonist, decreased pulmonary injury. The results of this study provide the basis for a new paradigm to understand the pathogenesis of pulmonary inflammation and vaso-occlusion in SCD and have important translational therapeutic implications. Together, these data indicate that iNKT cells play a pivotal role in sustaining inflammation in NY1DD mice and that this mechanism may translate to human disease. By inhibiting CD1d-restricted NKT cell activation, it may be possible to reduce end-organ damage in SCD.

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PHD (Doctor of Philosophy)
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