T Cell Tolerance by DEC-205-mediated Islet Antigen Delivery to Dendritic Cells

Project: Research project

Project Details

Description

Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the
pancreatic islet βcells. NOD mice constitute an extensively studied model for T1D sharing many
characteristics with the human disease. Our knowledge of at least some of the βcell antigens targeted by T
cells in both NOD mice and T1D patients can now be used practically to develop antigen-based strategies to
interfere with pathogenic autoreactive T cell populations and to better understand and augment natural
tolerance induction pathways. Dendritic cells (DCs) are critical for the initiation of adaptive immune responses
to pathogens. However, in the steady-state, DCs present antigens to T cells in a tolerogenic manner and are
important for the establishment of peripheral tolerance. While this was known to be the case in mice that are
not prone to the development of autoimmunity, we recently evaluated this concept in the setting of a
spontaneous autoimmune disease. We delivered a mimotope peptide, recognized by the diabetogenic NODderived
CD8+ T cell clone AI4, to DCs in NOD mice using a peptide-linked antibody to the DC endocytic
receptor DEC-205. Proliferation of transferred antigen-specific T cells was initially observed, but this was
followed by deletion. Thus, selective antigen targeting of DCs leads to deletion of transferred autoreactive
CD8+ T cells even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. While
promising, a substantial quantity of additional investigation must be performed before the application of such
technology to patients with T1D. Our objectives are to move this strategy in a stepwise fashion to humanized
mouse models of increasing relevance to patients with T1D. Four Specific Aims are proposed:
Aim 1a. To determine whether targeting of CD8+ T cell epitopes of βcell antigens to steadystate
DCs via DEC-205 can result in deletion of endogenous antigen-specific T cells in HLA-A*0201-
transgenic NOD mice.
Aim 1b. To test the efficacy of antigen targeting to DCs for the prevention of T1D in HLAA*
0201-transgenic NOD mice.
Aim 2a. To target preproinsulin to DCs via DEC-205 and monitor the response of endogenous
CD8+ and CD4+ insulin-specific T cells in HLA-A*0201-transgenic NOD mice.
Aim 2b. To test the efficacy of preproinsulin targeting to DCs for the prevention of T1D in HLAA*
0201-transgenic NOD mice.
Aim 3. To determine whether human islet-reactive T cells can be tolerized in response to DEC-
205-mediated delivery of βcell antigens to DCs.
Aim 4. To determine the mechanisms responsible for the T cell tolerance observed in response
to DEC-205-mediated delivery of βcell antigens to dendritic cells.
StatusFinished
Effective start/end date6/1/105/31/12

Funding

  • National Institute of Allergy and Infectious Diseases: $282,200.00

ASJC

  • Molecular Medicine
  • Cancer Research
  • Immunology and Allergy
  • Immunology
  • Pharmaceutical Science

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