Prevention of “Humanized” Diabetogenic CD8 T-Cell Responses in HLA-Transgenic NOD Mice by a Multipeptide Coupled-Cell Approach

  1. David V. Serreze1
  1. 1The Jackson Laboratory, Bar Harbor, Maine
  2. 2Comprehensive Diabetes Center, University of Alabama Birmingham, Birmingham, Alabama
  3. 3St. Vincent’s Institute, Victoria, Australia
  4. 4Diabetes Division, University of Massachusetts Medical Center, Worcester, Massachusetts
  1. Corresponding author: David V. Serreze, dave.serreze{at}jax.org.

Abstract

OBJECTIVE Type 1 diabetes can be inhibited in standard NOD mice by autoantigen-specific immunotherapy targeting pathogenic CD8+ T-cells. NOD.β2mnull.HHD mice expressing human HLA-A2.1 but lacking murine major histocompatibility complex class I molecules develop diabetes characterized by CD8 T-cells recognizing certain autoantigenic peptides also targeted in human patients. These include peptides derived from the pancreatic β-cell proteins insulin (INS1/2 A2–10 and INS1 B5–14) and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP265–273 and IGRP228–236). Hence, NOD.β2mnull.HHD mice represent a model system for developing potentially clinically translatable interventions for suppressing diabetogenic HLA-A2.1–restricted T-cell responses.

RESEARCH DESIGN AND METHODS Starting at 4–6 weeks of age, NOD.β2mnull.HHD female mice were injected intravenously with syngeneic splenocytes to which various admixtures of the four above-mentioned peptides were bound by the cross-linking agent ethylene carbodiimide (ECDI).

RESULTS Treatment with such cells bearing the complete cocktail of INS and IGRP epitopes (designated INS/IGRP-SPs) significantly inhibited diabetes development in NOD.β2mnull.HHD recipients compared with controls receiving splenocytes coupled with an irrelevant HLA-A2.1–restricted Flu16 peptide. Subsequent analyses found syngeneic splenocytes bearing the combination of the two ECDI-coupled IGRPs but not INS peptides (IGRP-SPs or INS-SPs) effectively inhibited diabetes development in NOD.β2mnull.HHD mice. This result was supported by enzyme-linked immunospot (ELISPOT) analyses indicating combined INS/IGRP-SPs diminished HLA-A2.1–restricted IGRP but not INS autoreactive CD8+ T-cell responses in NOD.β2mnull.HHD mice.

CONCLUSIONS These data support the potential of a cell therapy approach targeting HLA-A2.1–restricted IGRP autoreactive CD8 T-cells as a diabetes intervention approach in appropriate human patients.

  • Received November 1, 2010.
  • Accepted January 4, 2011.

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  1. Diabetes vol. 60 no. 4 1229-1236
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