Activation of bone marrow adaptive immunity in type 2 diabetes: rescue by co-stimulation modulator Abatacept

Marianna Santopaolo, Niall Sullivan, Anita C Thomas, Valeria V Alvino, Lindsay B Nicholson, Yue Gu, Gaia Spinetti, Marinos Kallikourdis, Ashley W Blom, Paolo R Madeddu*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Background: Chronic low-grade inflammation and alterations in innate and adaptive immunity were reported in type 2 diabetes (T2D). Here, we investigated the abundance and activation of T cells in the bone marrow (BM) of patients with T2D. We then verified the human data in a murine model and tested if the activation of T cells can be rescued treating mice with Abatacept, an immunomodulatory drug employed for the treatment of rheumatoid arthritis. Clinical evidence indicated Abatacept can slow the decline in beta-cell function. Methods: A cohort of 24 patients (12 with T2D) undergoing hip replacement surgery was enrolled to the study. Flow-cytometry and cytokine analyses were performed on BM leftovers from surgery. We next compared the immune profile of db/db and control wt/db mice. In an additional study, db/db mice were randomized to receive Abatacept or vehicle for 4 weeks, with endpoints being immune cell profile, indexes of insulin sensitivity, and heart performance.
Results: T2D patients showed increased frequencies of BM CD4+ (2.8-fold, p=0.001) and CD8+ T cells (1.8-fold, p=0.01), with upregulation of the activation marker CD69 and homing receptor CCR7 in CD4+ (1.64-fold, p=0.003 and 2.27-fold, p=0.01, respectively) and CD8+ fractions (1.79-fold, p=0.05 and 1.69-fold, p=0.02, respectively). These differences were confirmed in a multivariable regression model. CCL19 (CCR7 receptor ligand) and CXCL10/11 (CXCR3 receptor ligands), implicated in T cell migration and activation, were the most differentially modulated chemokines. Studies in mice confirmed the activation of adaptive immunity in T2D. Abatacept reduced the activation of T cells and levels of pro-inflammatory cytokines, and improved cardiac function, but not insulin sensitivity.
Conclusions: Results provide proof-of-concept evidence for the activation of BM adaptive immunity in T2D. In mice, treatment with Abatacept dampens the activation of adaptive immunity and protects from cardiac damage.
Original languageEnglish
Article number609406
Number of pages25
JournalFrontiers in Immunology
Volume12
DOIs
Publication statusPublished - 4 Mar 2021

Structured keywords

  • Bristol Heart Institute

Keywords

  • diabetes
  • immunity
  • bone marrow
  • cardiovaacular
  • adipo/cytokines

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