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

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Hypothesis</jats:title><jats:p>Type 2 diabetes (T2D) is characterized by low-grade inflammation. Here, we investigated the state of adaptive immunity in bone marrow (BM) of patients and mice with T2D. We also tested if inhibition T cell co-stimulation by Abatacept could rescue the immune profile of T2D mice.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Flow-cytometry and cytokine analyses were performed on BM samples from patients with or without T2D. Moreover, we studied the immune profile of db/db and control wt/db mice. A cohort of db/db mice was randomized to receive Abatacept or vehicle for 4 weeks, with endpoints being immune cell profile and indexes of insulin sensitivity and heart performance.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>T2D patients showed increased frequencies of BM CD4<jats:sup>+</jats:sup> (2.8-fold, p=0.001) and CD8<jats:sup>+</jats:sup> T cells (1.8-fold, p=0.01), with upregulation of the activation marker CD69 and homing receptor CCR7 in CD4<jats:sup>+</jats:sup> (1.64-fold, p=0.003 and 2.27-fold, p=0.01, respectively) and CD8<jats:sup>+</jats:sup> fractions (1.79-fold, p=0.05 and 1.69-fold, p=0.02, respectively). 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 chemokines and cytokines. Additionally, Abatacept improved indexes of cardiac systolic function, but not insulin sensitivity.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>These novel findings support the concept of BM adaptive immune activation in T2D. Modulation of T cell co-stimulation could represent an attractive and immediately available modality to dampen inappropriate activation of adaptive immune response and protect from target organ damage.</jats:p></jats:sec>

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

“…A third type of bone marrow niche cell that has been linked to diabetes-induced inflammation are lymphoid cells which are more abundant in the bone marrow of type 2 diabetics. Abatacept, which inhibits T cell activation and shows clinical value in some type 1 diabetics [ 150 ] was able to reduce inflammation and improved cardiovascular function in a genetic model of diabetes [ 151 ]. Thus, in obesity and type 2 diabetes, the systemic environment is enriched in myeloid cells but unable to mobilize beneficial HSCs in response to stimuli, and the niche plays a vital role in these events [ 149 ].…”