Auotimmune myocarditis, which can occur after viral infection, underlies many cases of dilated cardiomyopathy. CD8+ cytolytic T lymphocytes mediate much of the damage in myocarditis, but the mechanisms by which naive CD8+ T cell tolerance is broken, and the regulation of autoreactive effector CD8+ T cells are incompletely understood. In this proposal, a newly developed transgenic model of myocarditis will be used to study the regulation of heart antigen-specific CD8+ T cells and to determine how several T cell costimulatory and inhibitory pathways influence disease. Mice that express the model antigen ovalbumin (cMy-mOva) will be used in conjunction with ovalbumin peptide-specific CD8+ T cells from the OT-1 TCR transgenic mouse. Adoptive transfer of activated OT-1 cells, or naive OT-I cells followed by infections with ovalbumin-expressing virus, causes myocarditis in cMy-mOva-ova mice. Disease can be assessed by histology, serum troponin levels, ultrasonography, and mortality. There are three Specific Aims in this proposal.
Specific Aim 1. Determine the role of CTLA-4 in regulation of heart-antigen specific CD+ T cells. CTLA-4 is a negative regulator of T cell activation, but little is known, about the role of this molecule in inhibiting autoreactive CD8+ T cells. In this Aim, the pathogenic potential and in vivo fate of CTLA-4+/+ and CTLA-4 OT-I cells in alpha MHC-ova mice will be compared.
Specific Aim 2. Determine the role of the PD-1:PD-L 1/2 pathway in CD8+ T cell-mediated myocarditis PD-1, a newly identified member of the CD28 family, inhibits effector functions of T cells when it binds its ligands PD-L1 and PD-L2. The role of this pathway in negatively regulating heart-antigen specific CD8+ T cells in vivo will be explored using PD-L1/L2 -/- cMy-mOva mice as recipients of OT-I cells.
Specific Aim 3. Determine the role of ICOS in CD8+ T cell-mediated myocarditis. ICOS, a member of the CD28 family of costimulatory molecules, may have particular importance in sustaining activation of effector T cells. In this Aim, the pathogenic potential, effector functions, and in vivo fate of ICOS -/- and ICOS +/+ OT-I cells will be compared in the cMy-mOva mouse model of myocarditis. This project will provide new information about the regulation of autoreactive CD8+ T cells, and will clarify how CD8+ T cell responses against myocardial antigens are controlled. The focus is on newly characterized T cell regulatory pathways, which are potential targets for immunotherapy of myocarditis and other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072056-04
Application #
7076177
Study Section
Immunobiology Study Section (IMB)
Program Officer
Massicot-Fisher, Judith
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$388,120
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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