Cardiovascular disease (CV) is a major cause of hospitalization and mortality. Recent work has shown that inflammation plays a major role in atherogenesis and in Dilated Cardiomyopathy (DCM), a condition that leads to cardiac fibrosis and heart failure(HF). Yet clinical trials aiming to control this pathogenic inflammation via blocking of effector cytokines have failed, possibly due to the varied roles of the cytokines. An emerging therapeutic strategy for immune-mediated diseases is Adoptive Cell Therapy (ACT) with T cells, which can specifically modulate immune responses that contribute to pathology. Adoptive T cell therapy (ACT) is a promising technique based on the therapeutic administration of selective T cell populations, which can achieve a more specific modulation of the immune response. Regulatory T cells (Treg) are the naturally occurring suppressors of undesirable or deleterious immune responses. Treg administration is protective in different mouse models of cardiac disease, whilst chronic HF in humans is associated with defects in Treg. Treg have also been shown to limit the development of atherosclerosisin mice.Treatment of cardiovascular diseases via ACT with anti-inflammatory regulatory T cells (Treg) has already produced encouraging results in animal models. Current ACT protocols lack targeting of the transferred cells to their site of action, which reduces efficacy. The site of inflammation recruits pro-inflammatory cells via secretion of chemokines. We have shown that retrovirally expressing chemokine receptors on the transferred Treg that match these chemokines, forces the Treg to preferentially home to the target tissue. We hypothesize that retrovirally transducing chemokine receptors that match the chemokines preferentially expressed at the site of inflammation in dilated cardiomyopathy and atherosclerosis will enable the directed homing of transduced Treg to the site of inflammation. The Treg should suppress the ongoing immune response and thus slow down/block disease progression.
We propose to use chemokine receptor-modified Treg in ACT as a proof-of-concept therapeutic strategy in models of DCM and severe atherosclerosis.
