New insights into the role of VIP on the ratio of T‐cell subsets during the development of autoimmune diabetes

Abstract

Type I diabetes is an autoimmune T-cell-mediated disease associated with overexpression of inflammatory mediators and the disturbance of different T-cell subsets. Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent with regulatory effects on activated T cells. As the equilibrium between different T-cell subsets is involved in the final outcome, leading to tolerance or autoimmunity, we studied the evolution of markers for T cells in nonobese diabetic (NOD) mice. The study of different transcription factors, cytokines or cytokine receptors, shows that VIP interferes with functional phase of T helper 17 (Th17) cells and prevents the increase in the proportion of Th1 to Th17 cells. On the other hand, VIP-treated NOD mice show an increase in the proportion of CD4 + CD25 + cells in the spleen. Thus, VIP switches the Tregs/Th17 ratio leading to tolerance in NOD mice. Similarly, VIP reverses the ratio of Th1-/Th2-cell subsets associated with autoimmune pathology. All these effects on the ratio of T-cell subsets and the anti-inflammatory effect of VIP in decreasing proinflammatory mediators result in a reduction of b-cell destruction in pancreas. Taken together, these results show that VIP provides significant protection against spontaneous diabetes by modulating T-cell subsets and counterbalancing tolerance and immunity. Keywords: vasoactive intestinal peptide; NOD mice; type I diabetes; Th17; T-cell subsets; regulatory T cell Human type I diabetes (T1D) is an autoimmune disease that results from the destruction of pancreatic insulin-producing b-cells. 1,2 The autoimmune response is believed to be due to a breakdown of immunological tolerance, resulting in a lack of immunoregulation of autoreactive diabetogenic T cells. The nonobese diabetic (NOD) mouse is a strain that is genetically prone to develop different, organspecific, autoimmune diseases. It has been a very useful model for studying the mechanisms involved in the initiation and propagation of T1D. 3 In NOD mice, islet antigens first appear in the pancreatic lymph nodes at around 2-4 weeks of age; autoreactive effectors T cells are sensitized and then infiltrate the islets. 4 Progression to overt disease occurs in 80% of female mice between 10 and 30 weeks and it results from T-cell-mediated islet destruction.T helper (Th) cells have been classified into different functional subsets, each characterized by its specific cytokine pattern and effector function. 5 The Th1 subset is thought to be a crucial player in most organ-specific autoimmunity, including T1D, in which type I cytokines (interferon-g (IFNg), interleukin-2 (IL-2) and tumor necrosis factor-a (TNFa)) predominate over type II (Th2) and regulatory (Tregs) cytokines (IL-4 and IL-10). Two important classes of Tregs within the CD4 + T-cell subset are CD4 + CD25 + Foxp3 + Tregs and T-regulatory type I (Tr1) cells, that differ in a number of biological features. There are two major categories of CD4 + CD25 + Foxp3 + Tregs, the naturally occurring CD4 + CD25 + Foxp3 + Tregs from the thymus...

Decoding the chemokine network that links leukocytes with decidual cells and the trophoblast during early implantation

“…It binds to G protein coupled receptors VPAC1 and VPAC2 with potent immunomodulatory and trophic effects on adult and embryonic tissues. [27][28][29][30][31][32][33][34][35][36][37] At the maternal-placental interface, VIP localize in first and third trimester placenta in the syncytium and extravillous cytotrophoblast cells. 38 VIP dose-dependently stimulated hCG production from human primary cultured trophoblast cells as well as choriocarcinoma cell line JEG-3.…”

Vasoactive intestinal peptide/vasoactive intestinal peptide receptor relative expression in salivary glands as one endogenous modulator of acinar cell apoptosis in a murine model of Sjögren's syndrome

“…Reverse-transcribed cDNAs were amplified using specific primers for VIP, VPAC1, VPAC2, bax, TNF-a and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) and conditions as stated previously [16,[24][25][26][27]. The following sequences were used for forward and reverse primers.…”

“…PCR products were size-fractionated on 2% agarose gels and visualized by staining with ethidium bromide using a size molecular marker. For real-time experiments, VIP and TNF-a expression were determined as described [26,27].…”

Inflammatory Mediators Alter Interleukin-17 Receptor, Interleukin-12 and -23 Expression in Human Osteoarthritic and Rheumatoid Arthritis Synovial Fibroblasts: Immunomodulation by Vasoactive Intestinal Peptide

“…Vasoactive intestinal peptide (VIP) is a peptide shared by the neuroendocrine-immune network that modulates innate and adaptive immunity through binding to its G-protein-coupled specific receptors VPAC1 and VPAC2. This modulation leads to the amelioration or prevention of several inflammatory and autoimmune disorders in animal models, including septic shock and RA [10,11,12,13,14,15,16]. Since VIP was described as a beneficial endogenous mediator in collagen-induced arthritis [16], intense interest has been focused on translational research in humans.…”