Manipulation of CD98 resolves type 1 diabetes in nonobese diabetic mice

J Immunol. 2012 Mar 1;188(5):2227-34. doi: 10.4049/jimmunol.1102586. Epub 2012 Jan 30.

Abstract

The interplay of CD4(+) and CD8(+) T cells targeting autoantigens is responsible for the progression of a number of autoimmune diseases, including type 1 diabetes mellitus (T1D). Understanding the molecular mechanisms that regulate T cell activation is crucial for designing effective therapies for autoimmune diseases. We probed a panel of Abs with T cell-modulating activity and identified a mAb specific for the H chain of CD98 (CD98hc) that was able to suppress T cell proliferation. The anti-CD98hc mAb also inhibited Ag-specific proliferation and the acquisition of effector function by CD4(+) and CD8(+) T cells in vitro and in vivo. Injection of the anti-CD98hc mAb completely prevented the onset of cyclophosphamide-induced diabetes in NOD mice. Treatment of diabetic NOD mice with anti-CD98hc reversed the diabetic state to normal levels, coincident with decreased proliferation of CD4(+) T cells. Furthermore, treatment of diabetic NOD mice with CD98hc small interfering RNA resolved T1D. These data indicate that strategies targeting CD98hc might have clinical application for treating T1D and other T cell-mediated autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / therapeutic use
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cyclophosphamide / administration & dosage
  • Diabetes Mellitus, Type 1 / chemically induced
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Female
  • Fusion Regulatory Protein 1, Heavy Chain / genetics
  • Fusion Regulatory Protein 1, Heavy Chain / immunology
  • Fusion Regulatory Protein 1, Heavy Chain / physiology*
  • Growth Inhibitors / genetics
  • Growth Inhibitors / metabolism
  • Growth Inhibitors / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Rats
  • Rats, Wistar

Substances

  • Antibodies, Monoclonal
  • Fusion Regulatory Protein 1, Heavy Chain
  • Growth Inhibitors
  • ILAT protein, rat
  • Slc3A2 protein, mouse
  • Cyclophosphamide