Peptide-pulsed immature dendritic cells reduce response to beta cell target antigens and protect NOD recipients from type I diabetes

Ann N Y Acad Sci. 2006 Oct;1079:153-6. doi: 10.1196/annals.1375.023.

Abstract

Our previous work demonstrated peptide-pulsed mature myeloid dendritic cells (DC) presenting beta cell antigens induce tolerance. Here we determine whether immature DC (iDC) presenting dominant (insulin beta9-23 chain, proinsulin C19-A3) or ignored (glutamic acid decarboxylase 65(78-97)) antigen determinants promote tolerance. Nonobese diabetic (NOD) mice were given injections of either unpulsed or peptide-pulsed myeloid iDC beginning at 9 weeks of age for 3 consecutive weeks. Diabetes incidence in recipients of unpulsed iDC was comparable to unmanipulated animals ( approximately 80%), whereas GAD65(78-97) pulsed iDC recipients were protected from the disease (P = 0.05). We also analyzed splenic T cell proliferation responses to the panel of studied peptides in diabetic and nondiabetic recipients. When stimulated with insulin or proinsulin peptide, nondiabetic mice receiving the peptide-pulsed iDC had a 21- to 31-fold or 3.9- to 9.0-fold reduction in T cell response, respectively, as compared to the response of diabetic unpulsed recipients. However, only a 2.6- to 3.1-fold reduction in response to beta chain peptide, and a 1.5- to 3.4-fold reduction in proinsulin response were observed in diabetic mice receiving peptide-pulsed iDC. The reduction was not specific to the immunizing peptide, as reduced proliferation was observed to other diabetes-target peptides. We conclude that protective iDC-based therapies require target antigen presentation, and ignored determinants may be preferable perhaps due to an available naïve T cell repertoire. In addition, iDC presenting peptides induce a nonspecific reduction in T cell responses to beta cell antigens, possibly through the induction of regulatory T cells.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer*
  • Animals
  • Antigens / immunology*
  • Cell Division / drug effects
  • Cell Division / immunology
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Dendritic Cells / transplantation
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Female
  • Glutamate Decarboxylase / immunology
  • Immune Tolerance
  • Insulin / pharmacology
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred NOD
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • Peptide Fragments / pharmacology
  • Spleen / cytology
  • Spleen / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / physiology

Substances

  • Antigens
  • Insulin
  • Peptide Fragments
  • Glutamate Decarboxylase