The development of autoimmune diseases is associated with presentation of self-antigens by dendritic cells (DCs) and sustained activation of auto-reactive T lymphocytes. The presence of self-reactive T cells in the periphery requires regulatory mechanisms to maintain self-tolerance. DCs are important in regulating both immunity and tolerance. In human blood, at least three types of precursors generate DCs with different efficiency to induce T cell activation. DCs express different types of receptors for antigen uptake. The nature of DC and the type of receptor involved in antigen uptake modulate the efficiency of antigen presentation to T cells. Approaches to block cytolytic T lymphocyte (CTL)-mediated responses in autoimmune diseases require the discovery of new strategies for induction of tolerogenic DCs. A newly described DC type (MDC8), derived from CD141xwCD16 hi monocyte precursors, represents the most potent DC subtype for priming CD8+ T cells.
Our specific aims will investigate mechanisms to reprogram presentation of antigenic peptides by MDCSs to induce tolerance. We will probe the efficiency of MDC8s to capture antigenic peptides and expand specific CD8+ T cells. Differences in receptor-mediated MDC8 activation states and differences in autocrine cytokine production will be addressed. We will examine the ability of MDCSs to induce tolerance and investigate conditions that de-activate MDC8 and lead to CDS+ T cell tolerization. Our scope is to explore the potential to induce tolerogenic MDC8s to be used for deletion of antigen-specific CTLs as a therapeutic approach in autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR050643-02
Application #
6804732
Study Section
Special Emphasis Panel (ZAR1-RJB-A (O1))
Program Officer
Gretz, Elizabeth
Project Start
2003-09-25
Project End
2005-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$85,000
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
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Stefanescu, Radu N; Olferiev, Mikhail; Liu, Yi et al. (2004) Inhibitory Fc gamma receptors: from gene to disease. J Clin Immunol 24:315-26