Tuning immune tolerance with vasoactive intestinal peptide: A new therapeutic approach for immune disorders

Abstract

The induction of immune tolerance is essential for the maintenance of immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure self-tolerance, including central clonal deletion, cytokine deviation and induction of regulatory T cells. Identifying the factors that regulate these processes is crucial for the development of new therapies of autoimmune diseases and transplantation. The vasoactive intestinal peptide (VIP) is a well-characterized endogenous anti-inflammatory neuropeptide with therapeutic potential for a variety of immune disorders. Here we examine the latest research findings, which indicate that VIP participates in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors. KeywordsInflammation; Autoimmunity; Regulatory T cells; Tolerance; Neuroimmunology; Neuropeptide Immune tolerance versus autoimmunityProtection against infection is fundamental to the survival of all complex organisms. The successful elimination of most pathogens requires crosstalk between the innate and adaptive arms of the immune system. The innate immune system recognizes pathogen-associated molecular signatures through pattern-recognition receptors, such as Toll-like receptors (TLRs), which induce the release of pro-inflammatory cytokines, chemokines and free radicals, the recruitment of inflammatory cells to the site of infection, and the lysis of infected host cells by natural killer cells and cytotoxic T lymphocytes. Although critical for the successful elimination of pathogens, the inflammatory process needs to be limited, since an excessive response can result in severe inflammation and collateral tissue damage. Inflammatory responses also increase the risk of inducing harmful autoimmune responses, where immune cells and the molecules that respond to pathogen-derived antigens also react to self-antigens. *Corresponding Author: Mario Delgado, Instituto de Parasitologia y Biomedicina, CSIC, Avd. Conocimiento, PT Ciencias de la Salud, Granada 18100, Spain. Phone: 34-958-181665. Fax: 34-958-181632. email: mdelgado@ipb.csic.es Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptPeptides. Author manuscript; available in PMC 2008 September 1. Published in final edited form as:Peptides. 2007 September ; 28(9): 1833-1846. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Aut...

Genetic association of vasoactive intestinal peptide receptor with rheumatoid arthritis: Altered expression and signal in immune cells

“…VIP has recently emerged as one of the endogenous factors involved in the maintenance of immune tolerance in RA and other autoimmune disorders (2)(3)(4)(5). In this study, we obtained the first evidence indicating that deficient expression of the VIP receptor VPAC 1 in immune cells of RA patients is associated with the predominant proinflammatory Th1 milieu found in this disease.…”

“…In addition, VIP inhibits Th1 responses, promotes immune tolerance by inducing generation of Treg cells, and has emerged as a promising factor in the treatment of autoimmune/inflammatory diseases (3,4). Indeed, VIP is very efficient at ameliorating the pathology of several experimental autoimmune disorders, including RA, ulcerative colitis, multiple sclerosis, type 1 diabetes, and uveoretinitis (2,3,5). The therapeutic effect of VIP is associated with reduction in the severity of the 2 main phases of these immune disorders: VIP impairs early events that are associated with the initiation and establishment of autoimmunity to self tissue components, as well as later phases that are associated with the evolving immune and destructive inflammatory responses (3).…”

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

“…The immunological actions of VIP are exerted through a family of receptors, consisting of VPAC 1 and type 2 VPAC (10,13,43), coupled to adenylate cyclase and the elevation of intracellular cAMP levels and subsequent protein kinase A (PKA) activation. To determine whether the cAMP/PKA pathway mediates the suppressive actions for VIP on human T cells described in this work, ϩ CD25 Ϫ T cells isolated from C57BL/6 mice were cultured with anti-CD3 and APCs in the absence (T control ) or presence of 10 Ϫ7 M VIP (T VIP ) for 4 days, extensively washed, and rested 3 days in medium containing IL-2.…”

“…Indeed, VIP has been used for the treatment of various experimental models of inflammatory and autoimmune diseases (12,13). The therapeutic effect of VIP was initially attributed to the down-regulation of a wide panel of inflammatory mediators and to the inhibition of autoreactive Th1 cells.…”

Monocytes from Sjögren's syndrome patients display increased vasoactive intestinal peptide receptor 2 expression and impaired apoptotic cell phagocytosis

“…VIP promotes anti-inflammatory and tolerogenic effects in several inflammatory and autoimmune disease models [30,[33][34][35][36][37]. Particularly in the NOD mouse model of SS, a local gene therapy with an adenoviral construct encoding VIP restored salivary secretion and reduced autoimmune markers [38].…”