Targeting Macrophage Folate Receptor-β for Diagnosis and Treatment of Autoimmune Myocarditis
We investigated folate receptor-{beta} (FR-{beta}) expressed on activated macrophages as a therapeutic and imaging target in autoimmune myocarditis (AIM). Treatment with a folate-aminopterin conjugate (EC2319) targeting FR-{beta}-positive macrophages significantly reduced macrophage infiltration compared to saline (5.23 {+/-} 2.84% vs. 1.24 {+/-} 0.66%, P < 0.001) in rat experimental AIM. After immunization, FR-{beta} targeting positron emission tomography (PET) tracer [18F]FOL detected myocardial inflammatory lesions and revealed reduction in inflammation following EC2319 treatment relative to saline or tumor necrosis factor-alpha inhibitor Etanercept [standardized uptake value (SUV) 1.07 {+/-} 0.22 vs. 2.38 {+/-} 0.90 vs. 2.59 {+/-} 0.56, P < 0.001]. [18F]FOL PET signal correlated with myocardial CD68-positive macrophage content (r = 0.720, P < 0.001). These findings demonstrate that EC2319 attenuates myocardial inflammation in AIM and underscore the pathogenic role of FR-{beta}-positive macrophages. [18F]FOL PET provides a noninvasive means of detecting myocardial inflammatory activity and therapeutic response. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/686077v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@18e9296org.highwire.dtl.DTLVardef@139b8b3org.highwire.dtl.DTLVardef@8d1a74org.highwire.dtl.DTLVardef@1c3f06d_HPS_FORMAT_FIGEXP M_FIG C_FIG