Background— Evidence for an association between Chlamydia pneumoniae infection and coronary artery disease (CAD) has been reported by numerous studies, cross-reactive heat shock protein (Hsp) antibody responses have been causally linked to CAD, and the severity of chlamydial disease pathogenesis correlates with Hsp serology. Our aim was to determine if chlamydial Hsp (cHsp) antibody responses are predictive of CAD. Methods and Results— Patients were recruited in a case-control study: 250 cases had angiographically significant CAD (stenosis ≥70%), and 250 controls had normal coronary arteries (stenosis <10%). Serum immunoglobulin G reactivity to Hsp10 and Hsp60 antigens (chlamydial, Escherichia coli , and human), and C pneumoniae whole organisms were measured by ELISA. Univariate analysis confirmed that classical CAD risk factors were predictors of CAD. Univariate analysis showed that cHsp60 ( P = 0.001, OR 3.9), cHsp10 ( P =0.045, OR 3.8), E coli Hsp60 ( P =0.04, OR 1.5) and C pneumoniae ( P =0.03, OR 1.8) ELISA optical density (OD) values were significantly different between cases and controls. Multivariate analysis found that only upper-quintile cHsp60 seroreactivity remained a significant predictor of CAD after controlling for classical CAD risk factors and seroreactivity to the other antigens (cHsp60 OD, P =0.005, OR 3.9 per OD unit; cHsp60 quintile, 5 versus 1 to 4; P =0.01, OR 2.1). Conclusions— The presence of elevated anti-cHsp60 immunoglobulin G antibodies, but not anti-human or anti– E coli homologs, was independently associated with CAD. This finding argues against previous suggestions that cross-reactive or autoimmune Hsp60 responses may contribute to disease progression. High anti-cHsp60 antibody response appears to identify the subset of patients with chlamydial infection and significant CAD.

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The ability to restrict low molecular weight compounds to the gastrointestinal (GI) tract may enable an enhanced therapeutic index for molecular targets known to be associated with systemic toxicity. Using a triazolopyrazine CSF1R inhibitor scaffold, a broad range of prodrugs were synthesized and evaluated for enhanced delivery to the colon in mice. Subsequently, the preferred cyclodextrin prodrug moiety was appended to a number of CSF1R inhibitory active parent molecules, enabling GI-restricted delivery. Evaluation of a cyclodextrin prodrug in a dextran sodium sulfate (DSS)-induced mouse colitis model resulted in enhanced GI tissue levels of active parent. At a dose where no significant depletion of systemic monocytes were detected, the degree of pharmacodynamic effect–measured as reduction in macrophages in the colon–was inferior to that observed with a systemically available positive control. This suggests that a suitable therapeutic index cannot be achieved with CSF1R inhibition by using GI-restricted delivery in mice. However, these efforts provide a comprehensive frame-work in which to pursue additional gut-restricted delivery strategies for future GI targets.