Background: Peritoneal B1a cells attenuate atherosclerosis by secreting natural polyclonal immunoglobulin M (IgM). Regulatory B cells expressing T-cell immunoglobulin mucin domain-1 (TIM-1) expanded through TIM-1 ligation by anti-TIM-1 monoclonal antibody (RMT1-10) induces immune tolerance.
Methods and results: We examined the capacity of RMT1-10 to expand peritoneal B1a cells to prevent atherosclerosis development and retard progression of established atherosclerosis. RMT1-10 treatment selectively doubled peritoneal B1a cells, tripled TIM-1+ B1a cells and increased TIM-1+IgM+interleukin (IL)-10+ by 3-fold and TIM-1+IgM+IL-10- B1a cells by 2.5-fold. Similar expansion of B1a B cells was observed in spleens. These effects reduced atherosclerotic lesion size, increased plasma IgM and lesion IgM deposits, and decreased oxidatively modified low-density lipoproteins in lesions. Lesion CD4+ and CD8+ T cells, macrophages and monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, expression of proinflammatory cytokines monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, IL1β, apoptotic cell numbers and necrotic cores were also reduced. RMT1-10 treatment failed to expand peritoneal B1a cells and reduce atherosclerosis after splenectomy that reduces B1a cells, indicating that these effects are B1a cell-dependent. Apolipoprotein E-KO mice fed a high-fat diet for 6 weeks before treatment with RMT1-10 also increased TIM-1+IgM+IL-10+ and TIM-1+IgM+IL-10- B1a cells and IgM levels and attenuated progression of established atherosclerosis.
Conclusions: RMT1-10 treatment attenuates atherosclerosis development and progression by selectively expanding IgM producing atheroprotective B1a cells. Antibody-based in vivo expansion of B1a cells could be an attractive approach for treating atherosclerosis.
Keywords: B1a cells; IgM; RMT1‐10; TIM‐1; atherosclerosis; immune system.
© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.