PubMed Health⌕ Search

Biomedical subjects

Mario Delgado

Publications and source records attributed to Mario Delgado.

At least 37 records · Page 2Linked to original sources

Protective role for plasmid DNA-mediated VIP gene transfer in non-obese diabetic mice.

Studies focused on the development of diabetes in NOD mice-a model for human type 1 diabetes-have revealed that an autoimmune inflammatory process is produced by the effect of Th1 cells and their secreted cytokines. DNA vaccination has been shown to be an effective method for modulating immunity in viral infections and experimental autoimmune diseases, including diabetes. VIP's immunomodulatory properties are partly mediated by skewing the pattern of cytokines from a proinflammatory response to an anti-inflammatory response. Using gene delivery to express VIP, we interfered in the immune process leading to diabetes in prone, cyclophosphamide-treated NOD mice. Our results extend the role of VIP in the control of immunoregulatory networks and open new perspectives for immunointervention through VIP-based gene therapy.

Animals↗

VIP protects Th2 cells by downregulating granzyme B expression.

Selective differentiation of Th1/Th2 effectors contributes to cell- or antibody-mediated immunity. Vasoactive intestinal peptide (VIP) induces Th2 responses by promoting Th2 differentiation and survival. Here we investigate the mechanisms of VIP-induced Th2 survival. Microarray and protein data indicate that VIP prevents the upregulation of granzyme B (GrB) in Th2, but not Th1 effectors. This is the first report of GrB expression and of its involvement in activation-induced apoptosis of T helper cells. The enhanced responsiveness of Th2 cells to VIP is probably due to the higher expression of VIP receptors and alternative signaling pathways. This study identifies GrB as a new significant player in Th1/Th2 activation-induced cell death, and characterizes the mechanisms for the protective effect of VIP on Th2 survival.

Apoptosis↗

Regulation of dendritic cell differentiation by vasoactive intestinal peptide: therapeutic applications on autoimmunity and transplantation.

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) involved in the defense of the body and in the maintenance of the immune tolerance. The regulation of their maturation, migration, and expression of stimulatory and costimulatory molecules has major consequences on the immune response. The endogenous factors that regulate DC function are poorly known. Vasoactive intestinal peptide (VIP) is a neuropeptide with potent anti-inflammatory actions. This anti-inflammatory profile is maintained partially through effects on DC differentiation/function. Thus, VIP has differential effects on DCs, depending on the differentiation and stimulatory states. Immature DCs treated with VIP exhibit increased CD86 expression and induce CD4(+) T cell proliferation. In addition, the CD4(+) T cells activated in vitro or in vivo by VIP-treated iDCs exhibit a Th2 phenotype. In contrast, VIP reduces both CD86 and CD80 expression on lipopolysaccharide (LPS)-stimulated DCs, and inhibits the capacity of DCs to induce in vitro or in vivo T cell proliferation. However, addition of VIP in the early states of DC differentiation results in the generation of DCs that cannot mature following inflammatory stimuli that exhibit a tolerogenic phenotype, characterized by low expression of costimulatory molecules (CD40, CD80, and CD86), low production of proinflammatory cytokines, increased production of IL-10, and capacity to induce regulatory T cells with suppressive actions. The effect of VIP on the DC-Treg axis represents an additional mechanism for their general anti-inflammatory role, particularly relevant in autoimmunity and transplantation.

Animals↗

Cortistatin as a potential multistep therapeutic agent for inflammatory disorders.

The induction of immune tolerance is critical for the prevention of autoimmunity and the maintenance of immune homeostasis. The identification of factors involved in the maintenance or restoration of such tolerance has become the focus of new therapies for inflammatory and autoimmune diseases. Cortistatin, a recently discovered cyclic neuropeptide related to somatostatin, has emerged as a potential endogenous antiinflammatory factor based on its production by, as well as its binding to, immune cells. Thus, cortistatin has been found to downregulate the inflammatory response mediated by activated macrophages. The present work reviews various recent studies involving different experimental models of sepsis, rheumatoid arthritis and inflammatory bowel disease, demonstrating that cortistatin treatment offers great benefits at both the clinical and pathological levels. These include the downregulation of both inflammatory and Th1-mediated autoimmune disease components and the emergence of regulatory T cells (Treg) that suppress autoreactive T cells, both of which contribute to the restoration of immune tolerance. While many questions need to be resolved, cortistatin appears to be an exciting and promising candidate for the treatment of several chronic inflammatory diseases and autoimmune disorders.

Animals↗

Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis: down-regulation of inflammatory and autoimmune responses.

Multiple sclerosis (MS) is a disabling inflammatory, autoimmune demyelinating disease of the central nervous system. Despite intensive investigation, the mechanisms of disease pathogenesis remain unclear, and curative therapies are unavailable for MS. The current study describes a possible new strategy for the treatment of MS, based on the administration of the vasoactive intestinal peptide (VIP), a well-known immunosuppressive neuropeptide. Treatment with VIP significantly reduced incidence and severity of experimental autoimmune encephalomyelitis (EAE), in a MS-related rodent model system. VIP suppressed EAE neuropathology by reducing central nervous system inflammation, including the regulation of a wide spectrum of inflammatory mediators, and by selectively blocking encephalitogenic T-cell reactivity. Importantly, VIP treatment was therapeutically effective in established EAE and prevented the recurrence of the disease. Consequently, VIP represents a novel multistep therapeutic approach for the future treatment of human MS.

Animals↗

Urocortin and adrenomedullin prevent lethal endotoxemia by down-regulating the inflammatory response.

Urocortin 1 (UCN) and adrenomedullin (AM) are two neuropeptides that have emerged as potential endogenous anti-inflammatory factors based on their production by and binding to immune cells. Because human septic shock involves excessive inflammatory cytokine production, we investigated the effect of UCN and AM in the production of inflammatory mediators and their therapeutic actions in two models of septic shock. Both peptides down-regulated the production of inflammatory mediators by endotoxin-activated macrophages. The administration of UCN or AM protected against lethality after cecal ligation and puncture or after injection of bacterial endotoxin and prevented septic shock-associated histopathology, such as infiltration of inflammatory cells and intravascularly disseminated coagulation in various target organs. The therapeutic effect of UCN and AM was mediated by decreasing the local and systemic levels of a wide spectrum of inflammatory mediators, including cytokines, chemokines, and the acute phase protein serum amyloid A. Importantly, UCN or AM treatment was therapeutically effective in established endotoxemia. In conclusion, UCN and AM could represent two multistep therapeutic agents for human septic shock to be used in combination with other immunomodulatory agents or complementary as anti-inflammatory factors to other therapies.

Adrenomedullin↗

The neuropeptide vasoactive intestinal peptide generates tolerogenic dendritic cells.

Tolerogenic dendritic cells (DCs) play an important role in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Treg). Endogenous factors contribute to the functional development of tolerogenic DCs. In this report, we present evidence that two known immunosuppressive neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), contribute to the development of bone marrow-derived tolerogenic DCs in vitro and in vivo. The VIP/PACAP-generated DCs are CD11c(low)CD45RB(high), do not up-regulate CD80, CD86, and CD40 following LPS stimulation, and secrete high amounts of IL-10. The induction of tolerogenic DCs is mediated through the VPAC1 receptor and protein kinase A, and correlates with the inhibition of IkappaB phosphorylation and of NF-kappaBp65 nuclear translocation. The VIP/PACAP-generated DCs induce functional Treg in vitro and in vivo. The VIP/DC-induced Treg resemble the previously described Tr1 in terms of phenotype and cytokine profile, suppress primarily Th1 responses including delayed-type hypersensitivity, and transfer suppression to naive hosts. The effect of VIP/PACAP on the DC-Treg axis represents an additional mechanism for their general anti-inflammatory role, particularly in anatomical sites which exhibit immune deviation or privilege.

Animals↗

Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo.

CD4+CD25+ regulatory T (Treg) cells control the immune response to a variety of antigens, including self-antigens, and several models support the idea of the peripheral expansion of CD4+CD25+ Treg cells. Although hormones such as estrogen and alpha-melanocyte-stimulating hormone have been recently reported to expand the CD4+CD25+ Foxp3-expressing Treg cell compartment, little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+CD25+ Treg cells. In this study, we report on the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, to induce functional Treg cells in vivo. The administration of VIP together with specific antigen to T cell receptor (TCR)-transgenic (Tg) mice results in the expansion of the CD4+CD25+, Foxp-3/neuropilin 1-expressing T cells, which inhibit responder T cell proliferation through direct cellular contact. In addition to the increase in the number of CD4+CD25+ Treg cells, VIP induces more efficient suppressors on a per-cell basis. The VIP-generated CD4+CD25+ Treg cells transfer suppression, inhibit delayed-type hypersensitivity in TCR-Tg hosts, and prevent graft-versus-host disease in irradiated hosts reconstituted with allogeneic bone marrow.

Animals↗

Vasoactive intestinal peptide induces regulatory dendritic cells with therapeutic effects on autoimmune disorders.

The induction of antigen-specific tolerance is critical for the prevention of autoimmunity and maintenance of immune tolerance. In addition to their classical role as sentinels of the immune response-inducing T cell reactivity, dendritic cells (DCs) play an important role in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Tr). The possibility to generate tolerogenic DCs opens new therapeutic perspectives in autoimmune/inflammatory diseases. Therefore, the characterization of the endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. In this study, we report on the use of the known immunosuppressive neuropeptide, the vasoactive intestinal peptide, as a new approach to induce tolerogenic DCs with capacity to generate Tr cells, to restore tolerance in vivo, and to reduce the progression of rheumatoid arthritis and experimental autoimmune encephalomyelitis.

Animals↗

Analysis of a GT microsatellite in the promoter of the foxp3/scurfin gene in autoimmune diseases.

The aim of this study was to assess the possible association of the functional (GT)(n) microsatellite polymorphism in the FOXP3 gene with predisposition to several autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ulcerative colitis (UC), Crohn's disease, and celiac disease. We analyzed a case-control cohort composed of 231 SLE patients, 293 RA patients, 528 inflammatory bowel disease (354 Crohn's disease patients and 260 UC patients) patients, 103 celiac disease patients, and 274 healthy controls ethnically matched. Genotyping of (GT)(n) microsatellite was performed by polymerase chain reaction (PCR)-based method combined with fluorescent technology. We found no evidence for association of this polymorphism between controls and these autoimmune disease patients. Additionally, no differences in the genotype and allele distribution were found when patients were stratified according to clinical manifestation. The (GT)(n) microsatellite of the FOXP3 gene may not play a relevant role in the susceptibility to SLE, RA, inflammatory bowel disease, and celiac disease in our population.

Arthritis, Rheumatoid↗

Vasoactive intestinal peptide family as a therapeutic target for Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with no effective protective treatment, characterised by a massive degeneration of dopaminergic neurons in the substantia nigra and the subsequent loss of their projecting nerve fibres in the striatum. Because current treatments for PD are not effective, considerable research has been focused recently on a number of regulatory molecules that regulate inflammation characteristic of PD, induce neurotrophic and survival factors and reduce oxidative stress. Vasoactive intestinal peptide (VIP), a neuropeptide with a potent anti-inflammatory, antiapoptotic and neurotrophic effect, has been found to be protective in several inflammatory disorders. This review examines the putative protective effect of VIP and analogues in different models for PD. VIP emerges as a potential valuable neuroprotective agent for the treatment of pathological conditions in the CNS, such as PD, in which inflammation-induced neurodegeneration occurs.

Antiparkinson Agents↗

Role of vasoactive intestinal peptide in inflammation and autoimmunity.

Vasoactive intestinal peptide (VIP), a peptide produced by immune cells, exerts a wide spectrum of immunological functions that control the homeostasis of the immune system. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, both in innate and adaptive immunity. In innate immunity, this peptide inhibits the production of inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP reduces the expression of co-stimulatory molecules on antigen-presenting cells, and therefore reduces stimulation of antigen-specific CD4 T-cells. In terms of adaptive immunity, VIP promotes T-helper (Th)2-type responses, and reduces inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors are known. Therefore, VIP and its analogs have been proposed as promising alternative candidates to existing therapies for the treatment of acute and chronic inflammatory and autoimmune diseases. The aim of this review is to update knowledge of the cellular and molecular events that are relevant to VIP function in the immune system. The central functions that VIP plays in cellular processes is being recognized and attention is being focused on this important peptide with regard to exciting new candidates for therapeutic intervention and drug development.

Animals↗

Survival on chronic dialysis: 10 years' experience of a single Colombian center.

Using a retrospective cohort study, we evaluated survival and mortality risk factors in our dialysis population at the Renal Unit, RTS Cauca--Nephrologic San Jose, Popaydn, Cauca, Colombia. In the study, we included patients with chronic renal failure who started dialysis therapy during the period 1994-1999, and who remained on dialysis for a minimum of 5 years. Endpoints (living, died, lost to follow-up) were evaluated at the end of the study (July 2004), and a Kaplan-Meier survival analysis was performed. Mortality risk was analyzed using the multivariate Cox proportional hazard model. The study included 236 patients (129 on peritoneal dialysis and 107 on hemodialysis), whose mean age (+/- standard deviation) was 54.5 +/- 15.6 years. Of the group, 51% were women, 68.7% were urban dwellers, and 31.3% were rural dwellers. Major causes of end-stage renal disease included chronic glomerulonephritis (43.2%), diabetic nephropathy (35.7%), and hypertensive nephropathy (6.0%). The racial origins of the study population were half-caste (80.7%), Afro-Colombian (8.8%), indigenous (7.6%), and white (2.6%). Median (+ standard error) survival on hemodialysis was 66 +/- 10 months. Median survival on peritoneal dialysis was 57 +/- 7 months. Among patients with diabetes, median survival on hemodialysis was 40 +/- 13 months, and on peritoneal dialysis, it was 38 +/- 4 months. Major causes of mortality included sudden death (40%), infection (25%), and cardiovascular causes (22.5%). Significant mortality risk factors for hemodialysis patients were congestive heart failure (p = 0.01) and albumin <3 g/dL (p = 0.01). For peritoneal dialysis patients, the significant risk factors were diabetes mellitus (p = 0.01) and albumin < 2.5 g/dL (p = 0.02). Patient survival in our setting is similar to that reported in other series. The strongest predictive factors for mortality were diabetes mellitus, congestive heart failure, anemia, and hypoalbuminemia.

Adolescent↗

VIP/PACAP preferentially attract Th2 effectors through differential regulation of chemokine production by dendritic cells.

The neuropeptides vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP) are potent immunomodulatory agents, acting as general anti-inflammatory factors. VIP, produced and secreted by Th2 cells following antigen stimulation, participates in a Th2 autoregulatory loop, promoting Th2-type responses through several nonexcluding mechanisms. VIP and PACAP affect the differentiation of CD4+ T cells directly and indirectly through antigen-presenting cells and promote the proliferation and/or survival of the Th2 effectors. Th1 and Th2 effectors express different chemokine receptors that control migration in response to various chemokines. In this study, we investigated the effects of VIP/PACAP on the production of CXCL10 (a Th1 chemokine) and of CCL22 (a Th2 chemokine) by bone marrow-derived dendritic cells. We found that VIP and PACAP inhibit CXCL10, while promoting CCL22 production, and that the effects are mediated through the VPAC1 receptor and involve cAMP/PKA as intracellular messengers. The induction of CCL22 and the suppression of CXCL10 in VIP/PACAP-treated dendritic cells results in the preferential chemoattraction of Th2 effectors both in vivo and in vitro. This is in agreement with the general Th2 bias induced by the two neuropeptides and adds an important parameter to their immunomodulatory function. By promoting Th2 migration, and preventing or reducing Th1 infiltration in inflammatory foci and sites of antigen presentation, VIP and PACAP help in resolving acute inflammatory processes and contribute to the prevention of chronic inflammation.

Animals↗

VIP/PACAP oppositely affects immature and mature dendritic cell expression of CD80/CD86 and the stimulatory activity for CD4(+) T cells.

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) released within lymphoid organs from nerve terminals and/or immune cells play a significant, anti-inflammatory role by inhibiting macrophage-induced inflammatory reactions and promoting T helper cell type 2 (Th2) responses. However, dendritic cells (DC) and not macrophages often are the major antigen-presenting cells and link between innate and adaptive immunity. The role of VIP/PACAP in DC development and function is mostly unknown. Here, we report that bone marrow-derived DC express VIP/PACAP receptors and that VIP and PACAP exert a differential effect on immature DC (iDC) and lipopolysaccharide (LPS)-treated DC. In iDC, VIP/PACAP up-regulates CD86 expression and enables them to stimulate T cell proliferation and differentiation into Th2 effectors in vivo and in vitro. In contrast, VIP/PACAP down-regulates CD80/CD86 expression in LPS-stimulated DC and strongly reduces their capacity to stimulate T cell proliferation and secretion of Th1 and Th2 cytokines. The VIP/PACAP effects on iDC and LPS-stimulated DC are mediated primarily through the VIP receptor 1. These results indicate that neuropeptides such as VIP and PACAP can differentially affect the function of iDC and mature DC. In the absence of an ongoing immune response, VIP/PACAP contributes to the initiation of Th2-type immunity, whereas in the presence of a full-blown, inflammatory reaction, VIP/PACAP act as anti-inflammatory agents.

Animals↗

The many faces of VIP in neuroimmunology: a cytokine rather a neuropeptide?

Neuroimmunomodulation has experienced an explosive growth not only in basic research, but expanding to the point that prospective clinical research could be now a reality. A crucial factor for the functioning of this intimate bidirectional network was the demonstration that the immune and neuroendocrine systems speak a mutual biochemical language. This implies 1) production of neuroendocrine hormones and neuropeptides by immune cells and of cytokines by neuroendocrine cells; 2) evidence for shared receptors on cells of the immune and neuroendocrine systems; 3) effect of neuroendocrine mediators on immune functions; and 4) effect of cytokines on the neuroendocrine system. This reduces traditional differences between neurotransmitters, hormones, and immune mediators and raises the following question: what can we now regard as immune or neuroendocrine? Vasoactive intestinal peptide (VIP) is one example of this paradigm. VIP has traditionally been classified as a neuropeptide/neurotransmitter based in its capacity to mediate and regulate neuronal functions. Recent work has demonstrated that VIP is produced by T cells, especially Th2 cells, and that through specific receptors it exerts immunological functions typically ascribed to Th2 cytokines in nervous and immune systems. Here, we postulate that instead of a neuropeptide, VIP could be fully considered a type 2 cytokine with a key role in neuroimmunology.

Allergy and Immunology↗

The significance of vasoactive intestinal peptide in immunomodulation.

First identified by Said and Mutt some 30 years ago, the vasoactive intestinal peptide (VIP) was originally isolated as a vasodilator peptide. Subsequently, its biochemistry was elucidated, and within the 1st decade, their signature features as a neuropeptide became consolidated. It did not take long for these insights to permeate the field of immunology, out of which surprising new attributes for VIP were found in the last years. VIP is rapidly transforming into something more than a mere hormone. In evolving scientifically from a hormone to a novel agent for modifying immune function and possibly a cytokine-like molecule, VIP research has engaged many physiologists, molecular biologists, biochemists, endocrinologists, and pharmacologists and it is a paradigm to explore mutual interactions between neural and neuroendocrine links in health and disease. The aim of this review is firstly to update our knowledge of the cellular and molecular events relevant to VIP function on the immune system and secondly to gather together recent data that support its role as a type 2 cytokine. Recognition of the central functions VIP plays in cellular processes is focusing our attention on this "very important peptide" as exciting new candidates for therapeutic intervention and drug development.

Adaptation, Physiological↗

Vasoactive intestinal peptide prevents activated microglia-induced neurodegeneration under inflammatory conditions: potential therapeutic role in brain trauma.

In most neurodegenerative disorders, including multiple sclerosis, Parkinson's disease, and Alzheimer's disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated microglia and its cytotoxic agents play a crucial pathologic role. Because current treatments for these diseases are not effective, several regulatory molecules termed "microglia-deactivating factors" recently have been the focus of considerable research. Vasoactive intestinal peptide (VIP) is a neuropeptide with a potent anti-inflammatory effect, which has been found to protect from other inflammatory disorders, such as endotoxic shock and rheumatoid arthritis. In the present study, we investigate the effect of VIP on inflammation-mediated neurodegeneration in vitro and in vivo as well as on the putative neuroprotective effect of VIP on experimental pathological conditions in which central nervous system (CNS) inflammation is involved, such as brain trauma. The involvement of activated microglia and their derived cytotoxic products is also studied. VIP has a clear neuroprotective effect on inflammatory conditions by inhibiting the production of microglia-derived proinflammatory factors (tumor necrosis factor alpha, interleukin-1beta, nitric oxide). In this sense, VIP prevents neuronal cell death following brain trauma by reducing the inflammatory response of neighboring microglia. Therefore, VIP emerges as a valuable neuroprotective agent for the treatment of pathologic conditions of the CNS where inflammation-induced neurodegeneration occurs.

Animals↗