ABSTRACT
Natural killer T cell antigen receptors (NKT TCRs) recognize lipid-based antigens (Ags) presented by CD1d. Although the TCR α-chain is invariant, NKT TCR Vß exhibits greater diversity, with one (Vß11) and three (Vß8, Vß7, and Vß2) Vß chains in humans and mice, respectively. With the exception of the Vß2 NKT TCR, NKT TCRs possess canonical tyrosine residues within complementarity determining region (CDR) 2ß that are critical for CD1d binding. Thus, how Vß2 NKT TCR docks with CD1d-Ag was unclear. Despite the absence of the CDR2ß-encoded tyrosine residues, we show that the Vß2 NKT TCR engaged CD1d-Ag in a similar manner and with a comparable affinity and energetic footprint to the manner observed for the Vß8.2 and Vß7 NKT TCRs. Accordingly, the germline-encoded regions of the TCR ß-chain do not exclusively dictate the innate NKT TCR-CD1d-Ag docking mode. Nevertheless, clear fine specificity differences for the CD1d-Ag existed between the Vß2 NKT TCR and the Vß8.2 and Vß7 NKT TCRs, with the Vß2 NKT TCR exhibiting greater sensitivity to modifications to the glycolipid Ag. Furthermore, within the Vß2 NKT TCR-CD1d-αGalCer complex, the CDR2ß loop mediated fewer contacts with CD1d, whereas the CDR1ß and CDR3ß loops contacted CD1d to a much greater extent compared with most Vß11, Vß8.2, and Vß7 NKT TCRs. Accordingly, there is a greater interplay between the germline- and nongermline-encoded loops within the TCR ß-chain of the Vß2 NKT TCR that enables CD1d-Ag ligation.
Subject(s)
Antigens, CD1d/immunology , Glycolipids/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Animals , Cloning, Molecular , Epitopes/genetics , Epitopes/immunology , Flow Cytometry , Glycolipids/metabolism , Mice , Mutagenesis , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Surface Plasmon ResonanceABSTRACT
BACKGROUND: Insulin, a high-risk medication, is prone to prescribing errors. Patients with diabetes experience higher hospitalization rates and extended hospital stays. Prescription errors, such as missing orders, inappropriate insulin type, missing instructions, and lack of appropriate intensification of insulin regimens are common issues. This project explored the use of system-based interventions and educational tools to minimize errors and improve the quality of insulin discharge regimens. METHODS: A needs assessment and baseline chart review were conducted before adapting a diabetes order set obtained from the University of California, San Diego. Subsequent beta testing and broader implementation were followed by repeat chart reviews to assess the impact. RESULTS: Providers strongly desired an insulin discharge order set, with 98% of those surveyed expressing this preference. Those who were high utilizers of the order set showed increased rates of ordering all supplies (55%), compared with pre-intervention rates (27%). However, no change was observed in the practice of intensifying insulin regimens in patients with uncontrolled diabetes upon discharge. DISCUSSION: Insulin prescribing is prone to error. A diabetes discharge order set may improve the percentage of patients who receive necessary insulin supplies at discharge and provide educational resources to encourage appropriate insulin regimens at hospital discharge.