Mobilization of regulatory T (Treg) cells from the spleen to the site of myocardial infarction can be promoted with the use of a CXC-chemokine receptor 4 (CXCR4) blocker, and the infiltrated Treg cells attenuate inflammatory gene expression in monocytes and macrophages and augment infarct repair. These findings come from a study in mice and pigs published in Circulation.
Intraperitoneal injection of the peptide macrocycle POL5551, a CXCR4 antagonist, into wild-type mice with reperfused myocardial infarction increased angiogenesis in the border zone of the infarct and decreased scar size, left ventricular remodelling and contractile dysfunction at 28 days. Administration of POL5551 was shown to mobilize Treg cells into the peripheral circulation, followed by accumulation of Treg cells in the myocardial infarct region. The treatment effects of POL5551 were absent in splenectomized wild-type mice, Treg cell-depleted DEREG mice and lymphocyte-deficient Rag1-knockout mice. In the infarct zone, the increased presence of Treg cells resulted in attenuated expression of inflammatory genes in monocytes and macrophages.
To test the translational potential of this approach, the researchers used a pig model of reperfused acute myocardial infarction. Intravenous injection of POL6326 (a clinical-stage analogue of POL5551) decreased infarct volume and improved left ventricular ejection fraction, measured using serial contrast-enhanced MRI.
“These findings should stimulate further research into the therapeutic potential of CXCR4 blockade after myocardial infarction and in other acute conditions wherein excessive innate and/or adaptive immune responses cause immunopathology,” conclude the researchers.
Wang, Y. et al. C-X-C motif chemokine receptor 4 blockade promotes tissue repair after myocardial infarction by enhancing regulatory T cell mobilization and immune-regulatory function. Circulation https://doi.org/10.1161/CIRCULATIONAHA.118.036053 (2019)
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Lim, G.B. Mobilizing regulatory T cells to promote myocardial repair. Nat Rev Cardiol 16, 200 (2019). https://doi.org/10.1038/s41569-019-0168-3