Characterization of the immune cell repertoire in myocardial infarction and heart failure
Myocardial infarction (MI) is the major cause of morbidity and mortality worldwide. The\nmost common cause of myocardial infarction is the partial or complete occlusion of\ncoronary arteries by the erosion or rupture of a vulnerable atherosclerotic plaque. MI\nis the prevailing cause of heart failur...
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| Formato: | Tesis de maestría acceptedVersion |
| Lenguaje: | Inglés |
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Facultad de Farmacia y Bioquímica
2019
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_5928 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_5928.dir/5928.PDF |
| Aporte de: |
| Sumario: | Myocardial infarction (MI) is the major cause of morbidity and mortality worldwide. The\nmost common cause of myocardial infarction is the partial or complete occlusion of\ncoronary arteries by the erosion or rupture of a vulnerable atherosclerotic plaque. MI\nis the prevailing cause of heart failure, which develops due to post-infarction left\nventricular remodeling, and therefore a huge problem in medical practice. Current\ntherapies are limited to mechanical revascularization strategies that restore blood flow,\nbut do not specifically target post-MI cardiac remodeling. Cardiac healing and\nremodeling are orchestrated, improved or aggravated, by cells of the immune system\nthat infiltrate the heart following myocardial infarction. Thus, immune-modulatory or\ncell-targeting strategies have been proposed in the combat against adverse cardiac\nremodeling, but the temporal and spatial parameters of cardiac immune cells are only\npartially understood.\nIn this thesis, I present a comprehensive cellular screening strategy by state-of-the-art\n15-color flow cytometry to define leukocyte infiltration in the heart. While recent studies\nhave focused on specific immune cell subsets, this study allows -for the first time- to\ndirectly compare leukocyte subsets from various hematopoietic lineages. In large parts\nmy results identify B cells, CD4+ T cells, and DCs as predominant lymphocytes\ninfiltrating the injured heart, while macrophages represent the most frequent\nleukocytes in the healthy heart. These results argue for an adaptive immune response\ninvolving antigen-presenting DCs and effector T and B cells. Indeed, cytokine profiles\nfrom cardiac lymphocyte showed an increase of TNF?, IFN?, IL-17, granzyme and\nGMCSF and the antigen-regulated activation marker CD40L at the late time-point 21\ndays after MI, which is consistent with the build-up of a relevant immune memory.\nAmong all regulated cell types, I identified potential new candidates, including NK cells\nthat peaked early only in the injured myocardium and ?/? T cells that represented a\nsmall population that infiltrated older ischemic section of the heart. Various control\nconditions, including models of non-ischemic heart injury by pressure-overload and\nnon-sustained ischemic injury by surgical ischemia/reperfusion (I/R) as well as the\nquantification of systemic leukocytes subsets suggest specificity of these findings.\nMy findings may inspire the functional evaluation of candidate cell subsets and\ncytokines in direct follow-up studies. These results may be helpful to establish novel\ncellular targets for future MI therapy. |
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