Nieves Varela

Human adipose-derived mesenchymal stem cells reduce inflammatory and T-cell responses and induce regulatory T cells in vitro in rheumatoid arthritis

Objectives: Adult mesenchymal stem cells were recently found to suppress effector T cell and inflammatory responses and have emerged as attractive therapeutic candidates for immune disorders. In rheumatoid arthritis (RA), a loss in the immunological self-tolerance causes the activation of autoreactive T cells against joint components and subsequent chronic inflammation. The aim of this study is to characterise the immunosuppressive activity of human adipose-derived mesenchymal stem cells (hASCs) on collagen-reactive T cells from patients with RA. Methods: The effects of hASCs on collagen-reactive RA human T cell proliferation and cytokine production were investigated, as well as effects on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes from patients with RA. Results: hASCs suppressed the antigen-specific response of T cells from patients with RA. hASCs inhibited the proliferative response and the production of inflammatory cytokines by collagen-activated CD4 and CD8 T cells. In contrast, the numbers of IL10-producing T cells and monocytes were significantly augmented upon hASC treatment. The suppressive activity of hASCs was cell-to-cell contact dependent and independent. hASCs also stimulated the generation of FoxP3 protein-expressing CD4+CD25+ regulatory T cells, with the capacity to suppress collagen-specific T cell responses. Finally, hASCs downregulated the inflammatory response and the production of matrix-degrading enzymes by synovial cells isolated from patients with RA. Conclusions: The present work identifies hASCs as key regulators of immune tolerance, with the capacity to suppress T cell and inflammatory responses and to induce the generation/activation of antigen-specific regulatory T cells.

Vasoactive intestinal peptide protects against β-amyloid-induced neurodegeneration by inhibiting microglia activation at multiple levels

Alzheimers disease (AD) is characterized by extracellular deposits of fibrillar β‐amyloid (Aβ) in the brain, increased microglial‐mediated inflammatory reactions in senile plaques, selective neuronal death, and cognitive deficits. The use of agents that limit microglial activation and inflammation in AD has recently emerged as an attractive therapeutic strategy for this disease. The vasoactive intestinal peptide (VIP), a widely distributed neuropeptide, has shown neuroprotective effects in acute brain damage in vivo and potent anti‐inflammatory actions in central nervous system. Here, we report that VIP inhibits Aβ‐induced neurodegeneration by indirectly inhibiting the production of a wide panel of inflammatory and neurotoxic agents by activated microglia cells. The inhibitory effect of VIP is mediated by blocking signaling through the p38 MAPK, p42/p44 MAPK, and NFkB cascades, the three major transduction pathways involved in the transcription of inflammatory mediators and the production of free radicals by Aβ‐activated microglia cells. Based on its neuroprotective action and its efficacy in inhibiting a broad range of inflammatory responses, VIP may provide a novel therapeutic approach to AD.

Therapeutic effect of cortistatin on experimental arthritis by downregulating inflammatory and Th1 responses

Background: Rheumatoid arthritis is a chronic autoimmune disease of unknown aetiology characterised by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. Aim: To propose a new strategy for the treatment of arthritis based on the administration of cortistatin, a newly discovered neuropeptide with anti-inflammatory actions. Methods: DBA/1J mice with collagen-induced arthritis were treated with cortistatin after the onset of disease, and the clinical score and joint histopathology were evaluated. Inflammatory response was determined by measuring the levels of various inflammatory mediators (cytokines and chemokines) in joints and serum. T helper cell type 1 (Th1)-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with collagen and by assaying the content of serum autoantibodies. Results: Cortistatin treatment significantly reduced the severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of cortistatin was associated with a striking reduction in the two deleterious components of the disease—that is, the Th1-driven autoimmune and inflammatory responses. Cortistatin downregulated the production of various inflammatory cytokines and chemokines, decreased the antigen-specific Th1-cell expansion, and induced the production of regulatory cytokines, such as interleukin 10 and transforming growth factor β1. Cortistatin exerted its effects on synovial cells through both somatostatin and ghrelin receptors, showing a higher effect than both peptides protecting against experimental arthritis. Conclusion: This work provides a powerful rationale for the assessment of the efficacy of cortistatin as a novel therapeutic approach to the treatment of rheumatoid arthritis.

Interferon-γ Sensitizes Human Myeloid Leukemia Cells to Death Receptor-mediated Apoptosis by a Pleiotropic Mechanism

The role of interferon (IFN)-γ as a sensitizing agent in apoptosis induced by ligation of death receptors has been evaluated in human myeloid leukemia cells. Incubation of U937 cells with IFN-γ sensitized these cells to apoptosis induced by tumor necrosis factor-α, agonistic CD95 antibody, and tumor necrosis factor-related apoptosis-inducing ligand. Other human myeloid leukemic cells were also sensitized by IFN-γ to death receptor-mediated apoptosis. Treatment of U937 cells with IFN-γ up-regulated the expression of caspase-8 and potently synergized with death receptor ligation in the processing of caspase-8 and BID cleavage. Concomitantly, a marked down-regulation of BCL-2 protein was also observed in cells incubated with IFN-γ. Furthermore, the caspase-dependent generation of a 23-kDa fragment of BCL-2 protein, the release of cytochrome c from mitochondria and the activation of caspase-9 were also enhanced upon death receptor ligation in IFN-γ-treated cells. Ectopically expressed Bcl-2 protein inhibited IFN-γ-induced sensitization to apoptosis. In summary, these results indicate that IFN-γ sensitizes human myeloid leukemic cells to a death receptor-induced, mitochondria-mediated pathway of apoptosis.

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

OBJECTIVE Vasoactive intestinal peptide (VIP) has been shown to be one of the endogenous factors involved in the maintenance of immune tolerance. Administration of VIP ameliorates clinical signs in various experimental autoimmune disorders. This study was undertaken to investigate whether the exacerbated inflammatory autoimmune response in rheumatoid arthritis (RA) might result directly from altered expression and/or signaling of VIP receptors in immune cells. METHODS The effect of specific agonists of different VIP receptors on collagen-induced arthritis in mice was investigated by clinical and histologic assessment and measurement of cytokine and chemokine production. Expression of VIP receptor type 1 (VPAC1) in synovial cells and monocytes from RA patients was determined by flow cytometry. Potential associations of VPAC1 genetic polymorphisms with RA susceptibility were investigated. RESULTS A VPAC1 agonist was very efficient in the treatment of experimental arthritis, and deficient expression of VPAC1 in immune cells of RA patients was associated with the predominant proinflammatory Th1 milieu found in this disease. Immune cells derived from RA patients were less responsive to VIP signaling than were cells from healthy individuals and showed reduced VIP-mediated immunosuppressive activity, rendering leukocytes and synovial cells more proinflammatory in RA. A significant association between multiple-marker haplotypes of VPAC1 and susceptibility to RA was found, suggesting that the reduced VPAC1 expression in RA-derived immune cells is associated with the described VPAC1 genetic polymorphism. CONCLUSION These findings are highly relevant to the understanding of RA pathogenesis. They suggest that VIP signaling through VPAC1 is critical to maintaining immune tolerance in RA. In addition, the results indicate that VPAC1 may be a novel therapeutic target in RA.

TUNING IMMUNE TOLERANCE WITH VASOACTIVE INTESTINAL PEPTIDE: A NEW THERAPEUTIC APPROACH FOR IMMUNE DISORDERS

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.

Tuning inflammation with anti-inflammatory neuropeptides

The immune system is confronted with the daunting task of defending the organism against invading pathogens while at the same time remaining self-tolerant to the body’s own constituents and preserving its integrity. The loss of immune tolerance stemming from an unbalance in pro-inflammatory factors versus anti-inflammatory cytokines, or of autoreactive/inflammatory T helper 1 cells versus regulatory/suppressive T cells, results in the breakdown of immune homeostasis and the subsidiary appearance of exacerbated inflammatory and autoimmune diseases. Some neuropeptides have been shown to have anti-inflammatory properties and to participate in maintaining immune tolerance. Here the authors examine the most recent developments in this field and highlight the effectiveness of using neuropeptides in treating several inflammatory and autoimmune disorders.

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.