Ethylenecarbodiimide-fixed splenocytes carrying whole islet antigens decrease the incidence of diabetes in NOD mice <i>via</i> down-regulation of effector memory T cells and autoantibodies

Abstract

Type 1 diabetes mellitus (T1DM) is a syndrome of loss of glucose homeostasis caused by the loss of β cell chronic autoimmunity against islet cells. Islet-specific epitopes coupled antigen presenting cells by Ethylenecarbodiimide (ECDI) is a promising strategy to induce antigen-specific tolerance. However, single epitope induced tolerance is insufficient to prevent the onset of T1DM. The aim of this study is to evaluate the efficacy of whole islet antigens in preventing the onset and progression of T1DM and identify the underlying immune mechanism in NOD mice. In this study, the whole islet antigens, derived from islet lysate isolated from BALB/c mice, were coupled to splenocytes of BALB/c mice by ECDI fixation (SP-Islet lysate), and then intravenously administrated to NOD mice. The results showed that, compared with control group, SP-Islet lysate group significantly decreased T1DM incidence and improved the survival of NOD mice. SP-Islet lysate treated mice had reduced insulitis score and autoantibody levels, and improved glucose tolerance and insulin/glucagon production. Furthermore, the effector memory T cells (T) were downregulated and regulatory T cells (Tregs) were upregulated by the SP-Islet lysate treatment, with reduced populations of Th1&Th17 cells. In conclusion, ECDI-fixed splenocytes carrying whole islet antigens effectively prevented the onset of T1DM in NOD mice, via suppressing the production of autoantibodies and inducing anergy of autoreactive T cells.

Vagotomy and Splenectomy Reduce Insulin Secretion and Interleukin-1β

“…Interestingly, the association between splenocytes and isolated pancreatic islets is able to protect islets from autoimmune attack in an in vitro model of diabetes mellitus type 1. 60 It is possible that ILs, produced by splenocytes, modulate the autonomic response in pancreatic islets. In fact, there is an intense bidirectional communication between the spleen and the autonomic system, determining their functional activity and influencing metabolic homeostasis.…”

Targeting Stem Cell-Derived Tissue-Associated Regulatory T Cells for Type 1 Diabetes Immunotherapy

“…Tregs can suppress the expression of CXC-chemokine receptor 3 (CXCR3) through T helper cells, resulting in subsequent absence of this cell infiltration in the pancreatic islets and ultimately prevent the movement of T effectors [14••, 64]. Additionally, Tregs could suppress autoimmune aggression in the pancreatic islets through regulating the inflammatory reaction (i.e., insulitis) [65, 66••]. Both IL-10 and TGF-β play a crucial role in regulating T1D [67, 68••].…”