VIP and Tolerance Induction in Autoimmunity

Rosignoli, Florencia; Torroba, M.; Juarranz, Yasmina; García-Gómez, María; Martı́nez, Carmen; Gomariz, Rosa P.; Pérez-Leirós, Claudia; Leceta, Javier

doi:10.1196/annals.1317.073

Cited by 37 publications

(53 citation statements)

References 17 publications

(27 reference statements)

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“…Reactive changes in CD25, CD62L and FOXP3 as phenotypic markers of putative Treg have been previously observed with immunomodulatory agents such as Cy, anti-IL-2, anti-CD25 and anti-CD3, and have been generally associated with positive outcome of immunomodulation in NOD mice [4,5,16,28]. A similar reactive increase in FOXP3 expression has recently been associated with beneficial effects of Treg activation achieved by several immunomodulatory modalities, including IL-2/IL-2 antibody complexes, anti-thymocyte globulin, complete Freund's adjuvant, vasoactive intestinal peptide and rapamycin [18,[40][41][42][43][44]. Considering the very different mechanisms of action of these agents, it can be proposed that dominance of CD25 − FOXP3 + T cells is mediated by superior survival and faster expansion.…”

Section: Discussionmentioning

confidence: 73%

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Yarkoni¹,

Kaminitz

Sagiv³

et al. 2009

Diabetologia

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Aims/hypothesis Interruption of IL-2 signalling is an attractive therapeutic target in autoimmune disorders. In this study we evaluated the effect of a fusion protein composed of IL-2 and caspase-3 (IL2-cas) on NOD mice, as compared with disease induction by cyclophosphamide. Methods IL2-cas was assessed in NOD mice at various ages and in conjunction with cyclophosphamide administration. The effect of IL2-cas on diabetogenic cells was evaluated in adoptive transfer experiments and in cell suspension in vitro. Results IL2-cas induced apoptosis in T cells expressing the α chain of the IL-2 receptor (cluster of differentiation [CD] 25) in vitro, with superior survival of T cells expressing CD4 and forkhead box P3 (FOXP3). The fusion protein decreased mixed lymphocyte reactivity, and pretreatment with IL2-cas decreased the efficacy of adoptive transfer of diabetes into NOD severe combined immunodeficiency mice. Administration of one dose of IL2-cas decreased the incidence of diabetes in NOD mice, showing a superior beneficial effect when administered at young age, and effectively blocked induction of hyperglycaemia by cyclophosphamide, reducing the severity of islet inflammation. Administration of IL2-cas caused an acute increase in CD25 -FOXP3 + T cells in the lymph nodes, pancreas and thymus in NOD mice, with similar effects in wild-type mice. Administration of IL2-cas after onset of hyperglycaemia resulted in superior survival. Conclusions/interpretation Targeted elimination of cells expressing the IL-2 receptor by this fusion protein disrupts the autoimmune pathogenesis in prediabetic and diabetic NOD mice, despite depletion of CD25 + regulatory T cells. Furthermore, this particular fusion protein is permissive to the development of FOXP3 + T cells that might contribute to protracted protection from the progression of insulitis and overt hyperglycaemia.

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Section: Discussionmentioning

confidence: 73%

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Yarkoni¹,

Kaminitz

Sagiv³

et al. 2009

Diabetologia

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Section: Immune Tolerance Versus Autoimmunitymentioning

confidence: 99%

“…Indeed, administration of VIP has been shown to delay the onset, decrease the frequency and/or severity of various experimental models of collagen-induced arthritis [15,43,99], inflammatory bowel disease [1], type I diabetes [55,73], multiple sclerosis [51,61], Sjogren's syndrome [63], pancreatitis [60], uveoretinitis [59] and keratitis [87]. VIP treatment impairs both early events, which are involved with the initiation and establishment of autoimmunity to self-tissue components, and the later phases, which are associated with the evolving immune and destructive inflammatory responses.…”

Section: Beneficial Effects Of Vip On Experimental Autoimmunitymentioning

confidence: 99%

“…Fourthly, VIP inhibits CD95 (FasL)-and granzyme B-mediated apoptosis of mouse T H 2 but not of T H 1 effector cells [30,81]. Finally, VIP induces the T H 2 master transcription factors c-MAF, GATA-3 and JUNB in differentiating murine CD4 + T cells, and inhibits T-bet, which is required for T H 1 cell differentiation [73,90]. Thus VIP regulates the T H 1/T H 2 balance by acting both directly on differentiating T cells and indirectly via the regulation of APC functions.…”

mentioning

confidence: 95%

“…Inflammatory responses are self-limited by anti-inflammatory mediators secreted by the host innate immune system, thus the ability to control an inflammatory state depends on the local balance between pro-and anti-inflammatory factors. However, recent evidence indicates that the adaptive immune system might also help to maintain immune tolerance during infection-induced immunopathology [73].In addition to central clonal deletion of self-reactive T cells in the thymus, the generation of antigen-specific regulatory T cells (Treg) plays a critical role in the induction of peripheral tolerance [5,83]. Thus unbalances between pro-inflammatory factors and anti-inflammatory cytokines, as well as between autoreactive/inflammatory T helper 1 (T H 1) cells and regulatory/ suppressive T cells, are central to the occurrence of inflammatory disorders and autoimmune diseases (Figure 1).…”

mentioning

confidence: 99%

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

et al. 2007

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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...

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Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

Juarranz

Gutiérrez‐Cañas

Santiago

et al. 2008

Arthritis & Rheumatism

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Objective. Vasoactive intestinal peptide (VIP) hasshown potent antiinflammatory effects in murine arthritis and ex vivo in human rheumatoid arthritis (RA) synovial cells. To investigate the potential endogenous participation of this system in the pathogenesis of RA, we analyzed the expression and regulation of VIP and its functional receptors in human fibroblast-like synoviocytes (FLS) from patients with osteoarthritis (OA) and patients with RA.Methods. The expression of VIP was studied by reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay, and immunofluorescence in cultured FLS, and by immunohistochemical analysis in synovial tissue. The expression and function of the potential VIP receptors in FLS were studied by RT-PCR, determination of intracellular cAMP production, cell membrane adenylate cyclase (AC) activity, and interleukin-6, CCL2, and CXCL8 production in response to VIP or specific agonists and antagonists.Results. VIP expression was detected in human FLS at the messenger RNA and protein levels, and it was significantly decreased in RA FLS compared with OA FLS. VIP receptor type 1 (VPAC 1 ) was the dominant AC-coupled receptor in OA FLS, in contrast with RA FLS, in which VPAC 2 was dominant. Tumor necrosis factor ␣-treated OA FLS reproduced the VIP and VPAC receptor expression pattern of RA FLS. The antagonistic effects of VIP on FLS proinflammatory factor production were reproduced by VPAC 1 -and VPAC 2 -specific agonists in OA FLS and RA FLS, respectively.Conclusion. VIP expression is down-regulated in RA and in tumor necrosis factor ␣-treated FLS, suggesting that down-regulation of this endogenous antiinflammatory factor may contribute to the pathogenesis of RA. In RA FLS, VPAC 2 mediates the antiinflammatory effects of VIP, suggesting that VPAC 2 agonists may be an alternative to VIP as antiinflammatory agents.The vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) system consists of 2 peptides and 3 receptors: VIP receptor type 1 (VPAC 1 ), VPAC 2 , and PACAP type 1 (PAC 1 ) receptor. These receptors belong to family 2 of the G proteincoupled receptors, which in recent years have shown remarkable antiinflammatory and immunomodulatory properties (1-3). VPAC 1 is constitutively expressed in macrophages and lymphocytes and binds VIP and PACAP with equal affinity (1,3). VPAC 2 has also been described in lymphocytes and macrophages as an inducible receptor after T cell receptor triggering or lipopolysaccharide (LPS) stimulation (1,3). The bestcharacterized effects of VIP/PACAP on immune cells are mediated by the adenylate cyclase (AC) pathway coupled to these receptors. Finally, the PAC 1 receptor is the PACAP-specific receptor, although at high concentrations VIP is a heterologous ligand (4). Endogenous VIP and PACAP can be produced by both neural and immune cells, but their regulation and participation in the pathogenesis of human inflammation are not known.

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VIP and Tolerance Induction in Autoimmunity

Cited by 37 publications

References 17 publications

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

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

Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

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