CLIO-(H-2K)-Lys-Tyr-Asp-Lys-Ala-Asp-Val-Phe-Leu

Type 1 diabetes (T1D) is an organ-specific autoimmune disease originating from the destruction of pancreatic β cells by autoreactive T cells (TCs) (1). In particular, islet-associated CD8 TCs initiate β cell insult and trigger shedding of β cell autoantigens. This subset of CD8 TCs is primarily restricted to the class I major histocompatibility complex (MHC) molecule H-2K (2), in which Vα17-Jα42 TC receptor α (TCR-α) chains are expressed for recognition of a unique β cell autoantigen (1), islet-specific glycose-6-phosphatase catalytic subunit-related protein (IGRP). After initiation, a series of immune responses occur, including loading autoantigens into antigen-presenting cells (the dendritic cells), activating autoreactive CD4 TCs, and infiltrating TCs in pancreatic islets. T1D development consists of an insulitis phase and a diabetes phase, which are readily reproduced in a murine model called non-obese diabetic (NOD) mouse for human T1D (3, 4). In general, the progression from insulitis to diabetes in NOD mice is accompanied by alternatively repeated circulation of IGRP–reactive CD8 TC pool and avidity maturation of its islet-associated counterpart (5). Thus, IGRP has been used as a target for human diabetogenic response. NOD peptide (NRP-V7) (Lys-Tyr-Asp-Lys-Ala-Asp-Val-Phe-Leu (KYNKANVEL)) is a mimotope of IGRP that shares a 67% sequence homology with the endogenous IGRP epitope and has high avidity for H-2K molecule (5). A transgenic mouse (8.3-NOD) that specifically expresses H-2K–restricted TCR (8.3-TCR) has been used for a variety of therapeutic studies (6), in which 8.3-TCR constitutes as much as 30% to 40% of islet-associated CD8 TCs (2). Cross-linked iron oxide-(H-2K)-(CLIO-NPR-V7) is a NRP-V7 labeled paramagnetic iron oxide nanoparticle that is used to image 8.3-TCR by magnetic resonance imaging (MRI) (1, 5). This agent consists of three components: an iron oxide nanoparticle core for MRI contrast enhancement, two avidin molecules are covalently linked to the core surface, and eight biotinylated peptide/MHC complex (NRP-V7/H-2K) monomers bind on the avidins for recognition of 8.3-TCR. The nanoparticle contains an icosahedral core of superparamagnetic crystalline FeO (magnetite) that is caged by epichlorohydrin cross-linked dextran and functionalized with amine groups (CLIO-NH) (7). They have a high magnetic susceptibility to induce a significant magnetization inside a magnetic field. This creates microscopic field gradients that diphase nearby protons and causes a shortening of T relaxation times (8). Avidin is a tetrameric protein with a molecular mass of 68 KDa that is capable of strongly binding four biotins (association constant () = 1.7 × 10 M) (9). Because CLIO-NRP-V7 binds to the peripheral 8.3-TCR in the blood directly, it can be used to label islet-associated TCs for tracking through systemic administration (1, 5).