T cell costimulation blockade blunts pressure overload-induced heart failure

Abstract

Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade might be therapeutically exploited to treat HF.

Immunotherapy for cardiovascular disease

“…Yet many HF patients display HFpEF. We have recently shown that, surprisingly, in cardiac biopsies of both patients with HFrEF or HFpEF, T cell presence in the ailing myocardium appears to correlate with the degree of fibrosis, and thus with disease severity …”

“…The correlation between inflammation and cardiac dysfunction can be elegantly demonstrated in preclinical mouse models, such as the transverse aortic constriction (TAC) model, the gold‐standard preclinical model for HF . In order to visualize this correlation in an intuitive manner, we used recently generated and published data for the expression of cytokines in the myocardium of TAC‐operated mice at different time points of the disease. We performed a meta‐analysis, plotting an index of heart dysfunction (loss in percent fractional shortening, i.e., the decrease in pumping volume of the ventricle, measured by echocardiography; details on calculations shown in the figure legend) against an arbitrary index of inflammation (i.e., the ratio of cardiac mRNA expression of the proinflammatory cytokine IL‐6 to the anti‐inflammatory cytokine IL‐10) (Figure A).…”

“… The reversible link between inflammation and heart dysfunction . Meta‐analysis plot of the correlation between heart dysfunction and cardiac (left ventricle) inflammation on data from different models of cardiac hypertrophy, generated in Kallikourdis et al . (A) Correlation of heart dysfunction and cardiac inflammation in healthy mice, two models of physiological cardiac hypertrophy (AKT‐transgenic, AKT‐tg; exercised (running) mice) and TAC‐operated HF mice at 1 and 4 wk after operation.…”

“…In pathological contexts, Treg are recruited to sites of inflammation in an attempt to control and limit the inflammatory response; in many cases this recruitment may happen too late to successfully control the inflammatory response. This may be the case in the myocardium, where indeed Treg can be observed, yet they appear too late in the progression of the disease . On the other hand, depletion of Treg in atherosclerosis‐prone ApoE KO mice leads to increased plaque inflammation and infiltration of T cells and macrophages.…”

“…ACT is a very promising approach, yet it is currently an expensive and complex therapeutic strategy, not readily applicable in the clinic due to various due‐to‐be‐resolved issues . We have recently shown that Treg‐like, safe immunosuppression can be obtained in a manner that does not involve cell transfer . Treg exert their suppressive actions in a variety of ways, including by inhibiting the ability of APC to costimulate T cells.…”