Nasal vaccination with troponin reduces troponin specific T-cell responses and improves heart function in myocardial ischemia-reperfusion injury.
Myocardial ischemia with subsequent reperfusion (MI/R) can lead to significant myocardial damage. Ischemia initiates inflammation at the blood-microvascular endothelial cell interface and contributes significantly to both acute injury and repair of the damaged tissue. We have found that MI/R injury in mice is associated with a cellular immune response to troponin. Myocardial cells exclusively synthesize troponin and release the troponin into the bloodstream following injury. Mucosally administered proteins induce T cells that secrete anti-inflammatory cytokines such as IL-10 and transforming growth factor beta at the anatomical site where the protein localizes. We found that nasal administration of the three subunits of troponin (C, I and T isoforms), given prior to or 1 h following MI/R, decreased infarct size by 40% measured 24 h later. At 1.5 months following MI/R, there was a 50% reduction in infarct size and improvement in cardiac function as measured by echocardiography. Protection was associated with a reduction of cellular immunity to troponin. Immunohistochemistry demonstrated increased IL-10 and reduced IFN-gamma in the area surrounding the ischemic infarct following nasal troponin. Adoptive transfer of CD4+ T cells to mice from nasally troponin-treated mice 1 h after the MI/R decreased infarct size by 72%, whereas CD4+ T cells from IL-10-/- mice or nasally BSA-treated mice had no effect. Our results demonstrate that IL-10-secreting CD4+ T cells induced by nasal troponin reduce injury following MI/R. Modulation of cardiac inflammation by nasal troponin provides a novel treatment to decrease myocardial damage and enhance recovery after myocardial ischemia.
Frenkel
Dan
D
Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Pachori
Alok S
AS
Zhang
Lunan
L
Dembinsky-Vaknin
Adi
A
Farfara
Dorit
D
Petrovic-Stojkovic
Sanja
S
Dzau
Victor J
VJ
Weiner
Howard L
HL
D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology*; D016753:Interleukin-10 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D020033:Protein Isoforms / Q000276:immunology; D014336:Troponin / Q000008:administration & dosage* / Q000276:immunology; D014611:Vaccination
D020033:Protein Isoforms; D014336:Troponin; D016753:Interleukin-10; D007371:Interferon-gamma