Background Innate lymphoid cells type 2 (ILC2s) play critical homeostatic functions in peripheral tissues. ILC2s reside in perivascular niches and limit atherosclerosis development. Objectives ILC2s also reside in the pericardium but their role in postischemic injury is unknown. Methods We examined the role of ILC2 in a mouse model of myocardial infarction (MI), and compared mice with or without genetic deletion of ILC2. We determined infarct size using histology and heart function using echocardiography. We assessed cardiac ILC2 using flow cytometry and RNA sequencing. Based on these data, we devised a therapeutic strategy to activate ILC2 in mice with acute MI, using exogenous interleukin (IL)-2. We also assessed the ability of low-dose IL-2 to activate ILC2 in a double-blind randomized clinical trial of patients with acute coronary syndromes (ACS). Results We found that ILC2 levels were increased in pericardial adipose tissue after experimental MI, and genetic ablation of ILC2 impeded the recovery of heart function. RNA sequencing revealed distinct transcript signatures in ILC2, and pointed to IL-2 axis as a major upstream regulator. Treatment of T-cell–deficient mice with IL-2 (to activate ILC2) significantly improved the recovery of heart function post-MI. Administration of low-dose IL-2 to patients with ACS led to activation of circulating ILC2, with significant increase in circulating IL-5, a prototypic ILC2-derived cytokine. Conclusions ILC2s promote cardiac healing and improve the recovery of heart function after MI in mice. Activation of ILC2 using low-dose IL-2 could be a novel therapeutic strategy to promote a reparative response after MI.
Background In pre-clinical models of acute myocardial infarction (MI), mature B cells selectively mobilise inflammatory monocytes into the heart, leading to increased infarct size and deterioration of myocardial function. Anti-CD20 antibody-mediated depletion of B cells limited infarct size and improved cardiac function. Rituximab is a monoclonal antibody targeted against human B cells and has been used in the treatment of autoimmune diseases and cancers. However, its use in cardiovascular disease is untested and is currently contraindicated. Purpose We assessed the safety, feasibility and pharmacodynamic effect of rituximab given acutely to patients with ST-elevation MI (STEMI). Method RITA-MI was a prospective, open-label, dose-escalation, single-arm, phase 1/2a clinical trial, which tested rituximab administered as a single intravenous dose in patients with STEMI within 48 hours of symptom onset. Four escalating doses (200, 500, 700 and 1000mg) were used with 6 patients in each group. Follow-up was performed during initial inpatient stay; on days 6 and 14; and at 3 and 6 months. The primary endpoint was safety, whilst secondary endpoints were changes in B cells and their subsets, immune cell subsets, and cardiac and inflammatory biomarkers. [NCT:03072199] Results Overall, rituximab was well tolerated across all doses with the most common adverse event being gastrointestinal disturbance. This was due to the concomitant oral secondary prevention medication started after a STEMI. Five severe adverse events were reported, none of which were assessed as being related. Rituximab caused a mean 96.3% (95% CI 93.8–98.8%) depletion of B cell within 30 mins of the infusion starting across all dose groups. At 6 hours a rebound in B cells was seen in the 200, 500 and 700mg doses, likely related to the emigration of B cells from secondary lymphoid tissues. Maximal B cell depletion was seen at day 6, which was lower than baseline for all doses (p<0.001) (figure 1). B cell repopulation at 6months was dose-dependent. In addition, there was modulation of returning B cell subsets characterised by increased transitional B cells (figure 1C). Immunoglobulin (IgG, IgM and IgA) levels were not affected during follow-up. Rituximab also caused an acute and transient decrease in lymphocytes (both CD4+ and CD8+ T cells) and monocytes, whilst transiently increasing neutrophils at the 6-hour timepoint. Cardiac biomarkers showed a decrease in CRP and BNP. Clinical echocardiogram showed an increase in ejection fraction at follow up (mean increase in EF of 7.8% (95% CI 3.11–12.6)). Conclusion Rituximab appears safe and feasible when given in acute STEMIs. We have shown for the first time that depletion of B cells within 30mins of starting rituximab which demonstrates the biological plausibility of our treatment paradigm. Additional new insight into the mechanism of action of rituximab was found. This has led directly to the setting up of a phase 2b trial. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): European Union Research Council
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