Modulation of experimental autoimmune myocarditis with cytokine-myosin fusion proteins and novel cardiac peptides
Author
Reece, Shaun Patrick
Abstract
Infectious agents that induce cross-reactive myocarditic T cell responses may cause autoimmune inflammation of the heart, dilated cardiomyopathy (DCM), and heart failure. The purpose of this study was to evaluate the efficacy of GMCSF-Myosin fusion proteins as tolerogenic vaccines capable of inhibiting experimental autoimmune myocarditis (EAM). The fusion proteins were comprised of an N-terminal granulocyte macrophage-colony stimulating factor (GM-CSF) domain and a C-terminal cardiac myosin antigen domain. The antigenic domains Myosin 1052-1076 and Myosin 614-643 were chosen based on epitopes known to cause EAM in Lewis rats and BALB/c mice, respectively. Bioactivity of the cytokine domains for GMCSF-Myo1052 and GMCSF-Myo614 were confirmed with bone marrow proliferation assays. Enhanced antigen presentation was confirmed for GMCSF-Myo1052. Both fusion proteins were found to inhibit disease progression when given as a pretreatment before EAM induction. When administered after disease induction, GMCSF-Myo614 reduced the incidence of EAM. To investigate the mechanisms of these tolerogenic vaccines, a model of EAM was developed in C57BL/6 mice by evaluating a peptide (myosin 718-736) derived from the murine cardiac alpha myosin heavy chain and theorized to bind to H2-I-Ab. EAM was successfully induced in Interferon gamma receptor knockout (Ifgr1-/- ) mice on the C57BL/6 background. Defining the mechanisms by which Interferon-gamma (IFN-[gamma]) inhibits EAM on the C57BL/6 background is beyond the scope of this project, but it is hypothesized that T cell apoptosis or induction of T regulatory cells is involved. In conclusion, this study demonstrated the feasibility of using GMCSF-Myosin fusion proteins to inhibit EAM, and provides a new model of EAM on C57BL/6 background to explore the mechanisms by which GMCSF-Myosin fusion proteins mediate tolerance.
Date
2016-05-16
Citation:
APA:
Reece, Shaun Patrick. (May 2016).
Modulation of experimental autoimmune myocarditis with cytokine-myosin fusion proteins and novel cardiac peptides.
,
(),
-
. Retrieved from
http://hdl.handle.net/10342/6077
MLA:
Reece, Shaun Patrick.
"Modulation of experimental autoimmune myocarditis with cytokine-myosin fusion proteins and novel cardiac peptides". .
. (),
May 2016.
September 30, 2023.
http://hdl.handle.net/10342/6077.
Chicago:
Reece, Shaun Patrick,
"Modulation of experimental autoimmune myocarditis with cytokine-myosin fusion proteins and novel cardiac peptides," , no.
(May 2016),
http://hdl.handle.net/10342/6077 (accessed
September 30, 2023).
AMA:
Reece, Shaun Patrick.
Modulation of experimental autoimmune myocarditis with cytokine-myosin fusion proteins and novel cardiac peptides. .
May 2016;
():
.
http://hdl.handle.net/10342/6077. Accessed
September 30, 2023.
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