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.

Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBDs) are associated with uncontrolled innate and adaptive immunity against normal constituents, including commensal bacteria and microbial products. Mesenchymal stem cells (MSCs) suppress effector T cell responses and have beneficial effects in various immune disorders. This work investigates the therapeutic effects of human adipose-derived MSCs (hASCs) in various models of IBD and sepsis. METHODS: Acute and chronic colitis was induced in mice with dextran sulfate sodium. Sepsis was induced by caecal ligation and puncture or by endotoxin injection. Colitic and septic mice were treated intraperitoneally with hASCs or murine ASCs, and diverse disease clinical signs and mortality were determined. The levels of various inflammatory cytokines and chemokines, T helper 1(Th1)-type response and generation of regulatory T cells (Treg) were determined in affected organs. RESULTS: Systemic infusion of ASCs significantly ameliorated the clinical and histopathological severity of colitis, abrogating weight loss, diarrhoea and inflammation, and increasing survival. The therapeutic effect was associated with downregulation of the Th1-driven inflammatory responses. ASCs decreased a wide panel of inflammatory cytokines and chemokines and increased interleukin 10 (IL10), acting on macrophages. hASCs also impaired Th1 cell activation in both colonic mucosa and draining lymph nodes. The induction of IL10-secreting Treg was partially involved in the therapeutic effect of hASCs. Moreover, ASCs protected from severe sepsis by reducing the infiltration of inflammatory cells in various target organs and by downregulating the production of various inflammatory mediators. CONCLUSIONS: hASCs emerge as key regulators of immune/inflammatory responses in vivo and as attractive candidates for cell-based treatments for IBD and sepsis.

Neuropeptides kill African trypanosomes by targeting intracellular compartments and inducing autophagic-like cell death.

Trypanosoma brucei is the causative agent of African sleeping sickness. Available treatments are ineffective, toxic and susceptible to resistance by the parasite. Here we show that various endogenous neuropeptides act as potent antitrypanosome agents. Neuropeptides exerted their trypanolytic activity through an unusual mechanism that involves peptide uptake by the parasite, disruption of lysosome integrity and cytosolic accumulation of glycolytic enzymes. This promotes an energetic metabolism failure that initiates an autophagic-like cell death. Neuropeptide-based treatment improved clinical signs in a chronic model of trypanosomiasis by reducing the parasite burden in various target organs. Of physiological importance is the fact that hosts respond to trypanosome infection producing neuropeptides as part of their natural innate defense. From a therapeutic point of view, targeting of intracellular compartments by neuropeptides suppose a new promising strategy for the treatment of trypanosomiasis.

Therapeutic effect of urocortin and adrenomedullin in a murine model of Crohn's disease.

BACKGROUND AND AIMS: Urocortin 1 (UCN) and adrenomedullin (AM) are two recently discovered neuropeptides that, due to their distribution and binding to receptors in immune cells, have emerged as potential endogenous anti-inflammatory factors. Crohn's disease is a chronic debilitating disease characterised by a Th1 driven severe inflammation of the gastrointestinal tract. This study investigated the therapeutic effect of UCN and AM in a murine model of colitis. METHODS AND RESULTS: Treatment with UCN or AM ameliorated significantly the clinical and histopathological severity of the inflammatory colitis, abrogating body weight loss, diarrhoea, and inflammation, and increased the survival rate of colitic mice. The therapeutic effect was associated with downregulation of both inflammatory and Th1 driven autoimmune responses, including regulation of a wide spectrum of inflammatory mediators. In addition, partial involvement of interleukin 10 secreting regulatory cells in this therapeutic effect was demonstrated. Importantly, UCN or AM treatments were therapeutically effective in established colitis and avoided recurrence of the disease. CONCLUSIONS: This work identifies UCN and AM as two potent anti-inflammatory factors with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Consequently, both peptides represent novel multistep therapeutic approaches for the treatment of Crohn's disease and other Th1 mediated inflammatory diseases.

Therapeutic approaches of vasoactive intestinal peptide as an immunomodulatory cytokine / Aproximaciones terapéuticas al péptido intestinal vasoactivo como una citocina inmunomoduladora

Vasoactive intestinal peptide (VIP) is a neuropeptide produced by the lymphoid cells, which exerts a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. During the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, both in innate and adaptive immunity. In innate immunity, VIP inhibits the production of pro-inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP reduces the expression of costimulatory molecules on the antigen-presenting cells, and therefore reduces the activation of antigen-specific CD4+ T cells. In terms of adaptive immunity, VIP promotes Th2-type responses, and reduces the pro-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 perfectly known. Therefore, VIP and its analogues have been recently proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis, Parkinson’s disease, Crohn’s disease, or autoimmune diabetes. 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 that VIP plays in cellular processes is focusing our attention on this «very important peptide» as exciting new candidates for therapeutic intervention and drug development (AU)

El Péptido Intestinal Vasoactivo (VIP) es un neuropéptido producido por diferentes células inmunitarias, con un amplio abanico de funciones implicadas en el control homeostático del sistema inmunitario. Estos efectos son llevados a cabo a través de varios receptores específicos expresados en distintas células inmunocompetentes. En la última década, se ha identificado a VIP como un potente factor anti-inflamatorio, tanto en la inmunidad innata como en la adquirida. En la inmunidad innata, VIP inhibe la producción de citocinas y quimiocinas proinflamatorias por macró- fagos, microglía y células dendríticas. Además, VIP reduce la expresión de moléculas coestimuladoras en las células presentadoras de antígeno, reduciendo así la estimulación antígeno-específica de células T. En cuanto a la inmunidad adquirida, VIP favorece las respuestas tipo Th2 frente a las proinflamatorias tipo Th1. Actualmente se conocen perfectamente muchos de los mecanismos moleculares y celulares implicados en esta regulación. Por lo tanto, se ha propuesto recientemente a VIP y análogos como candidatos muy prometedores, alternativos a terapias existentes, en el tratamiento de varias enfermedades autoinmunitarias e inflamatorias crónicas, tales como shock endotóxico, artritis reumatoide, esclerosis múltiple, enfermedad de Parkinson y de Crohn, y diabetes tipo I. El principal objetivo de esta revisión es primeramente actualizar nuestro conocimiento sobre los procesos celulares y moleculares relevantes en la función inmunitaria de VIP, y en segundo lugar, reunir todos los datos recientes que sustentan la hipótesis de que este «very important peptide» podría ser considerado una citocina tipo 2 candidato en el diseño futuro de nuevas terapias inmunomoduladoras (AU)

LYT1 protein is required for efficient in vitro infection by Trypanosoma cruzi.

Trypanosoma cruzi invasion of host cells involves several discrete steps: attachment, parasite internalization mediated by recruitment and fusion of host cell lysosomes, and escape from the parasitophorous vacuole to liberate amastigotes to multiply freely in the cytosol. This report describes the initial characterization of the LYT1 gene and the demonstration that the gene product is involved in cell lysis and infectivity. Mutational analysis demonstrated that deletion of LYT1 resulted in attenuation of infection, which was associated with diminished hemolytic activity. Reintroduction of LYT1 restored infectivity in null mutants, confirming the critical role of LYT1 in infection. Additionally, in vitro stage transition experiments with LYT1-deficient lines showed that these parasites converted to extracellular amastigote-like cells and metacyclic trypomastigotes more rapidly than wild-type parasites, suggesting that the diminished infectivity was not a result of the LYT1 deficiency that affected the parasite's ability to complete the life cycle.