Isolation of a nuclease-resistant decoy RNA that selectively blocks autoantibody binding to insulin receptors on human lymphocytes.
An RNA containing 2'-amino pyrimidines has been isolated using in vitro selection techniques that specifically and avidly (apparent Kd approximately 30 nM) binds a mouse monoclonal antibody called MA20. This 2'-amino-derivatized RNA is at least 10,000-fold more stable than unmodified RNA in serum, and can act as a decoy and block MA20 binding to its natural antigen, the human insulin receptor, on lymphocytes. Furthermore, this RNA decoy can inhibit MA20-mediated downmodulation of insulin receptor expression on human lymphocytes in culture by up to 90%. Surprisingly, the decoy RNA cross-reacts with autoantibodies from patients with extreme insulin resistance and can inhibit these antiinsulin receptor antibodies from downmodulating insulin receptor expression by up to 80% without impeding insulin binding to its receptor. These results suggest that in vitro-selected decoy RNAs may be able to specifically and selectively block oligoclonal autoimmune responses to self-antigens in patients with autoimmune diseases.
Lee
S W
SW
Department of Experimental Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Sullenger
B A
BA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D001667:Binding, Competitive; D015536:Down-Regulation; D006801:Humans; D007333:Insulin Resistance; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D012313:RNA / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D012313:RNA; D011972:Receptor, Insulin; D012260:Ribonucleases