Neuroendocrine Immunoregulation in Multiple Sclerosis

Currently, it is generally accepted that multiple sclerosis (MS) is a complex multifactorial disease involving genetic and environmental factors affecting the autoreactive immune responses that lead to damage of myelin. In this respect, intrinsic or extrinsic factors such as emotional, psychological, traumatic, or inflammatory stress as well as a variety of other lifestyle interventions can influence the neuroendocrine system. On its turn, it has been demonstrated that the neuroendocrine system has immunomodulatory potential. Moreover, the neuroendocrine and immune systems communicate bidirectionally via shared receptors and shared messenger molecules, variously called hormones, neurotransmitters, or cytokines. Discrepancies at any level can therefore lead to changes in susceptibility and to severity of several autoimmune and inflammatory diseases. Here we provide an overview of the complex system of crosstalk between the neuroendocrine and immune system as well as reported dysfunctions involved in the pathogenesis of autoimmunity, including MS. Finally, possible strategies to intervene with the neuroendocrine-immune system for MS patient management will be discussed. Ultimately, a better understanding of the interactions between the neuroendocrine system and the immune system can open up new therapeutic approaches for the treatment of MS as well as other autoimmune diseases

Immunomodulatory Effects of 1,25-Dihydroxyvitamin D on Dendritic Cells Promote Induction of T Cell Hyporesponsiveness to Myelin-Derived Antigens

Altres ajuts: This work was supported by positive discussion through the A FACTT network (Cost Action BM1305: http://www.afactt.eu/). COST is supported by the EU Framework Programme Horizon 2020. Further support was provided by Grant no. G.0168.09 of the Fund for Scientific Research-Flanders, Belgium (FWO-Vlaanderen), by an applied biomedical research project of the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT-TBM 140191), by the grants of the University of Antwerp through the Special Research Fund (BOF), a BOF-GOA grant (ID PS 28313), Medical Legacy Fund, the Methusalem funding programme, the Belgian Hercules Foundation, by grants of the Charcot Foundation, Belgium, and of the "Belgische Stichting Roeping," Belgium, ∑. The authors also thank the NIH AIDS Research and Reference Reagent Programme for providing the CMV pp65 peptide pool. WaiPing Lee held a Ph.D. fellowship of the Flemish Institute for Science and Technology (IWT).While emerging evidence indicates that dendritic cells (DC) play a central role in the pathogenesis of multiple sclerosis (MS), their modulation with immunoregulatory agents provides prospect as disease-modifying therapy. Our observations reveal that 1,25-dihydroxyvitamin D (1,25(OH)D) treatment of monocyte-derived DC results in a semimature phenotype and anti-inflammatory cytokine profile as compared to conventional DC, in both healthy controls and MS patients. Importantly, 1,25(OH)D-treated DC induce T cell hyporesponsiveness, as demonstrated in an allogeneic mixed leukocyte reaction. Next, following a freeze-thaw cycle, 1,25(OH)D-treated immature DC could be recovered with a 78% yield and 75% viability. Cryopreservation did not affect the expression of membrane markers by 1,25(OH)D-treated DC nor their capacity to induce T cell hyporesponsiveness. In addition, the T cell hyporesponsiveness induced by 1,25(OH)D-treated DC is antigen-specific and robust since T cells retain their capacity to respond to an unrelated antigen and do not reactivate upon rechallenge with fully mature conventional DC, respectively. These observations underline the clinical potential of tolerogenic DC (tolDC) to correct the immunological imbalance in MS. Furthermore, the feasibility to cryopreserve highly potent tolDC will, ultimately, contribute to the large-scale production and the widely applicable use of tolDC

Dendritic Cells: Cellular Mediators for Immunological Tolerance

In general, immunological tolerance is acquired upon treatment with non-specific immunosuppressive drugs. This indiscriminate immunosuppression of the patient often causes serious side-effects, such as opportunistic infectious diseases. Therefore, the need for antigen-specific modulation of pathogenic immune responses is of crucial importance in the treatment of inflammatory diseases. In this perspective, dendritic cells (DCs) can have an important immune-regulatory function, besides their notorious antigenpresenting capacity. DCs appear to be essential for both central and peripheral tolerance. In the thymus, DCs are involved in clonal deletion of autoreactive immature T cells by presenting self-antigens. Additionally, tolerance is achieved by their interactions with T cells in the periphery and subsequent induction of T cell anergy, T cell deletion, and induction of regulatory T cells (Treg). Various studies have described, modulation of DC characteristics with the purpose to induce antigen-specific tolerance in autoimmune diseases, graft-versus-host-disease (GVHD), and transplantations. Promising results in animal models have prompted researchers to initiate first-in-men clinical trials. The purpose of current review is to provide an overview of the role of DCs in the immunopathogenesis of autoimmunity, as well as recent concepts of dendritic cell-based therapeutic opportunities in autoimmune diseases

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Relapse is a major problem in acute myeloid leukemia (AML) and adversely impacts survival. In this phase II study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms’ tumor 1 (WT1) mRNA as post-remission treatment in 30 AML patients at very high risk of relapse. There was a demonstrable anti-leukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which are sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in non-responders (53.8% vs. 25.0%; P=0.01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25% and the 5-year relapse-free survival was higher in responders than in non-responders (50% vs. 7.7%; P65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared to 51.7% and 18% in the Swedish Acute Leukemia Registry (SALR). Long-term clinical response was correlated with increased circulating frequencies of poly-epitope WT1-specific CD8+ T-cells. Long-term OS was correlated with interferon-γ+ and tumor necrosis factor-α+ WT1-specific responses in delayed type hypersensitivity-infiltrating CD8+ T-lymphocytes. In conclusion, vaccination of AML patients with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8+ T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224

Leveraging research infrastructure co-location to evaluate constraints on terrestrial carbon cycling in northern European forests

Integrated long-term, in-situ observations are needed to document ongoing environmental change, to “ground-truth” remote sensing and model outputs and to predict future Earth system behaviour. The scientific and societal value of in-situ observations increases with site representativeness, temporal duration, number of parameters measured and comparability within and across sites. Research Infrastructures (RIs) can support harmonised, cross-site data collection, curation and publication. Integrating RI networks through site co-location and standardised observation methods can help answers three questions about the terrestrial carbon sink: (i) What are present and future carbon sequestration rates in northern European forests? (ii) How are these rates controlled? (iii) Why do the observed patterns exist? Here, we present a conceptual model for RI co-location and highlight potential insights into the terrestrial carbon sink achievable when long-term in-situ Earth observation sites participate in multiple RI networks (e.g., ICOS and eLTER). Finally, we offer recommendations to promote RI co-location