Prediman K. Shah

Artificial intelligence–derived myosteatosis measurements from coronary artery calcium CT scans were strongly associated with the incidence of clinically diagnosed chronic obstructive pulmonary disease, outperforming emphysema-like lung as a predictive biomarker.

Active immunization with the apolipoprotein B-100 (ApoB-100) peptide P210 reduces experimental atherosclerosis. To advance this immunization strategy to future clinical testing, we explored the possibility of delivering P210 as an antigen using nanoparticles, given this approach has been used clinically. We first characterized the responses of T cells to P210 using PBMCs from patients with atherosclerotic cardiovascular disease (ASCVD). We then investigated the use of P210 in self-assembling peptide amphiphile micelles (P210-PAMs) as a vaccine formulation to reduce atherosclerosis in B6.129P2-Apoe ^tm1Unc /J ( ApoE ^–/– ) mice and P210’s potential mechanisms of action. We also generated and characterized a humanized mouse model with chimeric HLA-A*02:01/Kb in ApoE ^–/– background to test the efficacy of P210-PAM immunization as a bridge to future clinical testing. P210 provoked T cell activation and memory response in PBMCs of patients with ASCVD. Dendritic cell uptake of P210-PAM and its costaining with MHC-I molecules supported its use as a vaccine formulation. In ApoE ^–/– mice, immunization with P210-PAMs dampened P210-specific CD4 ⁺ T cell proliferative response and CD8 ⁺ T cell cytolytic response, modulated macrophage phenotype, and significantly reduced aortic atherosclerosis. Potential clinical relevance of P210-PAM immunization was demonstrated by reduced atherosclerosis in the humanized ApoE ^–/– mouse model. Our data support experimental and translational use of P210-PAM as a potential vaccine candidate against human ASCVD.

Despite growing evidence for the characteristic signs of Alzheimer's disease (AD) in the neurosensory retina, our understanding of retina–brain relationships, especially at advanced disease stages and in response to therapy, is lacking. In transgenic models of AD (APP_SWE/PS1_∆E9; ADtg mice), glatiramer acetate (GA) immunomodulation alleviates disease progression in pre‐ and early‐symptomatic disease stages. Here, we explored the link between retinal and cerebral AD‐related biomarkers, including response to GA immunization, in cohorts of old, late‐stage ADtg mice. This aged model is considered more clinically relevant to the age‐dependent disease. Levels of synaptotoxic amyloid β‐protein (Aβ)_1–42, angiopathic Aβ_1–40, non‐amyloidogenic Aβ_1–38, and Aβ₄₂/Aβ₄₀ ratios tightly correlated between paired retinas derived from oculus sinister (OS) and oculus dexter (OD) eyes, and between left and right posterior brain hemispheres. We identified lateralization of Aβ burden, with one‐side dominance within paired retinal and brain tissues. Importantly, OS and OD retinal Aβ levels correlated with their cerebral counterparts, with stronger contralateral correlations and following GA immunization. Moreover, immunomodulation in old ADtg mice brought about reductions in cerebral vascular and parenchymal Aβ deposits, especially of large, dense‐core plaques, and alleviation of microgliosis and astrocytosis. Immunization further enhanced cerebral recruitment of peripheral myeloid cells and synaptic preservation. Mass spectrometry analysis identified new parallels in retino‐cerebral AD‐related pathology and response to GA immunization, including restoration of homeostatic glutamine synthetase expression. Overall, our results illustrate the viability of immunomodulation‐guided CNS repair in old AD model mice, while shedding light onto similar retino‐cerebral responses to intervention, providing incentives to explore retinal AD biomarkers.

Purpose of Review Atherosclerosis is a complex disease process with lipid as a traditional modifiable risk factor and therapeutic target in treating atherosclerotic cardiovascular disease (ACVD). Recent evidence indicates that genetic influence and host immune response also are vital in this process. How these elements interact and modify each other and if immune response may emerge as a novel modifiable target remain poorly understood. Recent Findings Numerous preclinical studies have clearly demonstrated that hypercholesterolemia is essential for atherogenesis, but genetic variations and host immune-inflammatory responses can modulate the pro-atherogenic effect of elevated LDL-C. Clinical studies also suggest that a similar paradigm may also be operational in atherogenesis in humans. More importantly each element modifies the biological behavior of the other two elements, forming a triangular relationship among the three. Modulating any one of them will have downstream impact on atherosclerosis. Summary This brief review summarizes the relationship among lipids, genes, and immunity in atherogenesis and presents evidence to show how these elements affect each other. Modulation of immune response, though in its infancy, has a potential to emerge as a novel clinical strategy in treating ACVD.