Sumanth Prabhu, M.D.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.
In mouse experiments, University of Alabama at Birmingham scientists now have shown a way to hit an immunological “reset button” that ends that inappropriately sustained inflammation. This reset reverses the pathologic enlargement and pumping failure of the heart, and it suggests a therapeutic approach to treating human heart failure.
“To date, there have been no large-scale immunomodulatory or anti-inflammatory therapies for chronic heart failure successfully translated into clinical practice,” said Sumanth Prabhu, M.D., a cardiovascular disease physician and leader of the UAB research, published in the journal Circulation.
Researchers 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. This shows, Prabhu said, that dysfunctional T-reg cells play “an essential pathogenetic role in chronic ischemic heart failure.”
Restoring the proper function of T-regs in humans, he said, is “an appealing therapeutic target for the resolution of chronic inflammation in ischemic cardiomyopathy.”
In a previous study published last year, the UAB 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.
Some evidence from other researchers working on a different disease supported such a hypothesis — in autoimmune arthritis, the inflammatory microenvironment was shown to alter the phenotype of T-reg cells to a pro-inflammatory state that accelerated damage in the arthritic joint. However, the possibility of T-reg dysfunction had never been explored in chronic heart failure.
In the current Circulation paper, Prabhu and colleagues show that the Foxp3+ T-reg cells in their mouse heart-failure model were indeed dysfunctional. Those T-reg cells expressed pro-inflammatory cytokines and tumor-necrosis-factor-alpha receptor 1, and they had diminished immunomodulatory capability. The dysfunctional T-reg cells also prevented the growth of new capillaries and promoted pathological increase of fibrotic scar tissue in the failing heart.
Furthermore, the UAB researchers showed that the dysfunctional T-reg cells were essential for adverse left-ventricular remodeling. Essentiality was demonstrated by selectively ablating the dysfunctional T-reg cells at four weeks after inducing heart failure. Ablation was done 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.
At UAB, Prabhu is the Mary Gertrude Waters Chair of Cardiovascular Medicine. He also is director of the Division of Cardiovascular Disease, in the Department of Medicine, and director of the UAB Comprehensive Cardiovascular Center. He is also on the medical service of the Birmingham Veterans Affairs Medical Center, Birmingham, Alabama.
Co-authors with Prabhu on the paper, “Dysfunctional and pro-inflammatory regulatory T-lymphocytes are essential for adverse cardiac remodeling in ischemic cardiomyopathy,” are Shyam S. Bansal, Ph.D., Mohamed Ameen Ismahil, Ph.D., Mehak Goel, Ph.D., Guihua Zhou, M.D., Ph.D., Gregg Rokosh, Ph.D., and Tariq Hamid, Ph.D., all of the Division of Cardiovascular Disease, UAB Department of Medicine, and the UAB Comprehensive Cardiovascular Center.
Support came from American Heart Association grant 14POST20490323, National Institutes of Health grants HL132123 and HL125735, and Veterans Affairs grant BX002706.