The progression of heart failure following a heart attack is driven by sustained levels of chronic inflammation. Researchers have now demonstrated the importance of this inflammation through the targeted removal of a critical population of T cells in mice, cells that become inappropriately inflammatory after injury to heart tissue. This selective destruction of immune cells produces a reversal of detrimental remodeling of heart muscle, as well as improvement in other inflammation-linked aspects of heart failure, such as fibrosis in heart tissue. Interestingly, this approach seems to result in lasting effects, as the replacement T cells, newly generated by the body, do not provoke further inflammation. All in all, this is a very promising set of data.
A heart attack triggers an acute inflammatory response, followed by resolution of inflammation and wound healing. A severe heart attack, however, can cause chronic and sustained inflammation that leads to heart failure and death. Researchers have found that a group of immune cells called regulatory T-lymphocyte cells, or T-regs, appear to go rogue in heart failure. Instead of their normal job to resolve inflammation, the dysfunctional T-reg cells become pro-inflammatory and prevent the growth of new capillaries. Experimental removal of those dysfunctional T-reg cells from heart-failure mice acted as a reset button to reverse heart failure, and the replacement T-regs that the mice produced resolved inflammation.
In a previous study, researchers had seen that CD4+ T-cells - which include T-regs - were globally expanded and activated in mouse heart failure, and there was persistent inflammation and activation of effector T cells, despite the increased numbers of T-reg cells that normally should help resolve inflammation. This led to the hypothesis for the present work - that the T-reg cells in heart failure themselves become dysfunctional, pro-inflammatory and tissue-injurious, and that that altered phenotype contributes to sustained inflammation and the pathologic enlargement of the heart's main pumping chamber. Such enlargement is known as left-ventricular remodeling.
The current study shows that dysfunctional T-reg cells are essential for adverse left-ventricular remodeling. Researchers selectively ablated the dysfunctional T-reg cells four weeks after heart failure. Ablation was accomplished by giving diphtheria toxin to genetically engineered mice that have the diphtheria toxin receptor inserted into T cells at the Foxp3 gene site, or by giving the mice anti-CD25 antibodies. T-reg ablation reversed left-ventricular remodeling over the next four weeks. Also, ablation with antibody halted further increase in left-ventricular remodeling, while remodeling in the heart failure mice given a non-specific antibody continued to worsen. Ablation alleviated fibrosis and systemic inflammation in the heart, and it enhanced growth of new capillaries.
Importantly, the new T-reg cells produced by the mice after an ablation pulse were no longer pro-inflammatory - instead, they showed restoration of normal T-reg immunosuppressive capacity. Thus, ablation of the pathogenic and dysfunctional T-reg cells acted, in effect, as a reset that restored the mouse T-reg cells back to their normal immunomodulatory function.