Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice

Ding, Qing; Yeung, Melissa Y.; Camirand, Geoffrey; Zeng, Qiang; Akiba, Hisaya; Yagita, Hideo; Chalasani, Geetha; Sayegh, Mohamed H.; Najafian, Nader; Rothstein, David M.

doi:10.1172/jci46274

Cited by 412 publications

(492 citation statements)

References 43 publications

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“…Previous studies using RMT1‐10 treatment have been limited to short‐term treatment 14. We used a prolonged therapeutic strategy involving administration of RMT1‐10 every other day for 8 weeks whilst ApoE‐KO mice were fed an HFD.…”

Section: Resultsmentioning

confidence: 99%

“…Rat anti‐mouse TIM‐1 IgG2a RMT1‐10 (clone RMT1‐10, BioXcell) was used to stimulate TIM‐1 receptor and controlled with an isotype‐matched control rat anti‐mouse IgG2a Ab (Sigma) 14, 15. In the prevention study, ApoE‐KO mice received either RMT1‐10 or IgG control intraperitoneally (0.2 mg/mouse)14, 17 on alternate days during an 8‐week HFD.…”

Section: Methodsmentioning

confidence: 99%

“…In the prevention study, ApoE‐KO mice received either RMT1‐10 or IgG control intraperitoneally (0.2 mg/mouse)14, 17 on alternate days during an 8‐week HFD. In the intervention study,14, 17 ApoE‐KO mice fed an HFD for 6 weeks to establish atherosclerosis were treated with the same regimen of either RMT1‐10 or control IgG2a antibody while continuing an HFD for 8 weeks.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…TIM‐1 has recently been found to be predominantly expressed on regulatory B cells 14. Ligation of TIM‐1 by a low affinity anti‐TIM‐1 monoclonal antibody (RMT1‐10) promotes immune tolerance via IL‐10‐expressing B cells 14. Treatment also increases TIM‐1+ B cell numbers and the percentage of TIM‐1+ B cells expressing IL‐10 and IL‐4,14 preserving regulatory T cells but inhibiting CD4+ Th1 cell expansion 15.…”

Section: Introductionmentioning

confidence: 99%

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Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Hosseini

Kanellakis

et al. 2018

JAHA

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BackgroundPeritoneal 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 ResultsWe 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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Hosseini

Kanellakis

et al. 2018

JAHA

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Regulatory B Cells

Guzman‐Genuino

Diener

2018

Encyclopedia of Life Sciences

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B cells are best known for their ability to produce antibodies and instigate immune memory necessary for the protection of the host against foreign stimuli. However, certain subsets of B cells are increasingly shown to be capable of negative immune regulation by counteracting inflammation and suppressing the immune response. These cells are aptly termed ‘regulatory B cells’ or ‘Bregs’ and carry out their function by multiple mechanisms that include production of anti‐inflammatory cytokines and cognate interaction with other immune cells. Bregs are able to restore an immune response to homeostatic levels and as such play crucial roles in health conditions requiring suppression of inflammation and/or maintenance of tolerance such as in autoimmunity, graft tolerance, allergy, infection, cancer and pregnancy. Understanding how these potent and dynamic cells can be controlled in various immune situations offers a promising avenue for the development of novel prophylactic and immune therapy treatments. Key Concepts Regulatory B cells or Bregs are B‐cell subsets capable of downmodulating the immune response. Bregs can suppress the immune response by producing anti‐inflammatory cytokines such as IL‐10 and TGF‐β, or through cell–cell contact with other immune cells. Bregs can limit the severity and progression of autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis by recruiting regulatory T cells and inhibiting proinflammatory cytokine production by helper T cells. Higher Breg frequency in peripheral circulation is correlated with operational tolerance in transplantation patients. Bregs induce and promote allergen tolerance primarily through IL‐10 production. Bregs can inhibit the immune response to viral, bacterial and parasitic infections, thereby allowing pathogen survival and disease progression. Bregs in tumour sites can hinder effector immune cells from attacking and eliminating cancer cells. In pregnancy, Bregs are likely to play an important role in the induction of maternal tolerance necessary for the successful growth of semiallogeneic foetus.

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Mechanisms of Tolerance

Zeng

Strober

2015

Thomas’ Hematopoietic Cell Transplantation

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Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice

Cited by 412 publications

References 43 publications

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Regulatory B Cells

Mechanisms of Tolerance

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