Vitamin D3 Induces Ido+ Tolerogenic Dcs And Enhances Treg, Reducing The Severity Of Eae

Background: A growing body of evidence supports the hypothesis that vitamin D is an important environmental factor in the etiology of T-cell-mediated autoimmune diseases such as multiple sclerosis (MS). Aim: The purpose of this study was exploring the mechanisms underlying the beneficial effect of vitamin D3 in encephalomyelitis (EAE). Methods: We treated monophasic experimental autoimmune EAE, induced in Lewis rat, with vitamin D3 and adoptively transfer tolerogenic bone marrow-derived DCs generated in the presence of vitamin D3. Results: This study provides evidence that the in vivo administration of vitamin D3, as well as the adoptive transfer of vitamin D3-induced IDO+ immature/tolerogenic dendritic cells, leads to a significant increase in the percentage of CD4+CD25+Foxp3+ regulatory T cells in the lymph nodes in a rat model of MS, experimental autoimmune EAE. Concomitant with the increase in this cell population, there is a significant decrease in the number of autoreactive T cells in the central nervous system. Bone marrow-derived DCs cultivated in the presence of vitamin D3 present a tolerogenic profile with high IL-10, TNFα, and IDO expression and decreased MHC-II and CD80 expression. The adoptive transfer of IDO + DCs induces a significant increase in the percentage of CD4+CD25+Foxp3+ T cells in the lymph nodes, comparable with vitamin D3 treatment. Conclusion: These mechanisms contribute actively to the generation of a microenvironment in the lymph nodes that suppresses the activation of encephalitogenic T cells, resulting in the downregulation of the inflammatory response in the central nervous system. © 2013 Blackwell Publishing Ltd.194269277Hafler, D.A., Slavik, J.M., Anderson, D.E., O'Connor, K.C., De Jager, P., Baecher-Allan, C., Multiple sclerosis (2005) Immunol Rev, 204, pp. 208-231van der Mei, I.A., Ponsonby, A.L., Blizzard, L., Dwyer, T., Regional variation in multiple sclerosis prevalence in Australia and its association with ambient ultraviolet radiation (2001) Neuroepidemiology, 20, pp. 168-174Wallin, M.T., Page, W.F., Kurtzke, J.F., Multiple sclerosis in US veterans of the Vietnam era and later military service: Race, sex, and geography (2004) Ann Neurol, 55, pp. 65-71Cantorna, M.T., Hayes, C.E., DeLuca, H.F., 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis (1996) Proc Natl Acad Sci U S A, 93, pp. 7861-7864Spach, K.M., Hayes, C.E., Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice (2005) J Immunol, 175, pp. 4119-4126Becklund, B.R., Hansen Jr, D.W., Deluca, H.F., Enhancement of 1,25-dihydroxyvitamin D3-mediated suppression of experimental autoimmune encephalomyelitis by calcitonin (2009) Proc Natl Acad Sci U S A, 106, pp. 5276-5281Santos, L.M., al-Sabbagh, A., Londono, A., Weiner, H.L., Oral tolerance to myelin basic protein induces regulatory TGF-beta-secreting T cells in Peyer's patches of SJL mice (1994) Cell Immunol, 157, pp. 439-447Hou, S.W., Liu, C.Y., Li, Y.H., Fasudil ameliorates disease progression in experimental autoimmune encephalomyelitis, acting possibly through antiinflammatory effect (2012) CNS Neurosci Ther, 18, pp. 909-917Spach, K.M., Nashold, F.E., Dittel, B.N., Hayes, C.E., IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis (2006) J Immunol, 177, pp. 6030-6037Bettelli, E., Carrier, Y., Gao, W., Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells (2006) Nature, 441, pp. 235-238Langrish, C.L., Chen, Y., Blumenschein, W.M., IL-23 drives a pathogenic T cell population that induces autoimmune inflammation (2005) J Exp Med, 201, pp. 233-240Park, H., Li, Z., Yang, X.O., A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 (2005) Nat Immunol, 6, pp. 1133-1141O'Connor, R.A., Prendergast, C.T., Sabatos, C.A., Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis (2008) J Immunol, 181, pp. 3750-3754Muthian, G., Raikwar, H.P., Rajasingh, J., Bright, J.J., 1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis (2006) J Neurosci Res, 83, pp. 1299-1309Tang, J., Zhou, R., Luger, D., Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response (2009) J Immunol, 182, pp. 4624-4632Adorini, L., Penna, G., Dendritic cell tolerogenicity: A key mechanism in immunomodulation by vitamin D receptor agonists (2009) Hum Immunol, 70, pp. 345-352Mora, J.R., Iwata, M., von Andrian, U.H., Vitamin effects on the immune system: Vitamins A and D take centre stage (2008) Nat Rev Immunol, 8, pp. 685-698Hewison, M., Freeman, L., Hughes, S.V., Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells (2003) J Immunol, 170, pp. 5382-5390Piemonti, L., Monti, P., Sironi, M., Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells (2000) J Immunol, 164, pp. 4443-4451Szeles, L., Keresztes, G., Torocsik, D., 1,25-dihydroxyvitamin D3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype (2009) J Immunol, 182, pp. 2074-2083Correale, J., Ysrraelit, M.C., Gaitan, M.I., Vitamin D-mediated immune regulation in multiple sclerosis (2011) J Neurol Sci, 311, pp. 23-31Tang, Q., Bluestone, J.A., The Foxp3 +  regulatory T cell: A jack of all trades, master of regulation (2008) Nat Immunol, 9, pp. 239-244Awasthi, A., Carrier, Y., Peron, J.P., A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells (2007) Nat Immunol, 8, pp. 1380-1389Carrier, Y., Yuan, J., Kuchroo, V.K., Weiner, H.L., Th3 cells in peripheral tolerance. II. TGF-beta-transgenic Th3 cells rescue IL-2-deficient mice from autoimmunity (2007) J Immunol, 178, pp. 172-178Sakaguchi, S., Ono, M., Setoguchi, R., Foxp3 +  CD25 +  CD4 +  natural regulatory T cells in dominant self-tolerance and autoimmune disease (2006) Immunol Rev, 212, pp. 8-27Anderton, S.M., Liblau, R.S., Regulatory T cells in the control of inflammatory demyelinating diseases of the central nervous system (2008) Curr Opin Neurol, 21, pp. 248-254O'Connor, R.A., Anderton, S.M., Foxp3 +  regulatory T cells in the control of experimental CNS autoimmune disease (2008) J Neuroimmunol, 193, pp. 1-11Awasthi, A., Murugaiyan, G., Kuchroo, V.K., Interplay between effector Th17 and regulatory T cells (2008) J Clin Immunol, 28, pp. 660-670Barrat, F.J., Cua, D.J., Boonstra, A., In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines (2002) J Exp Med, 195, pp. 603-616Ureta, G., Osorio, F., Morales, J., Rosemblatt, M., Bono, M.R., Fierro, J.A., Generation of dendritic cells with regulatory properties (2007) Transplant Proc, 39, pp. 633-637Penna, G., Roncari, A., Amuchastegui, S., Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4(+)Foxp3(+) regulatory T cells by 1,25-dihydroxyvitamin D-3 (2005) Blood, 106, pp. 3490-3497Farias, A.S., Martins-de-Souza, D., Guimaraes, L., Proteome analysis of spinal cord during the clinical course of monophasic experimental autoimmune encephalomyelitis (2012) Proteomics, 12, pp. 2656-2662Farias, A.S., Talaisys, R.L., Blanco, Y.C., Regulatory T cell induction during Plasmodium chabaudi infection modifies the clinical course of experimental autoimmune encephalomyelitis (2011) PLoS ONE, 6, pp. e17849Ramsdell, F., Foxp3 and natural regulatory T cells: Key to a cell lineage? (2003) Immunity, 19, pp. 165-168Sucher, R., Fischler, K., Oberhuber, R., IDO and regulatory T cell support are critical for cytotoxic T lymphocyte-associated Ag-4 Ig-mediated long-term solid organ allograft survival (2012) J Immunol, 188, pp. 37-46O'Sullivan, B.J., Pai, S., Street, S., Immunotherapy with costimulatory dendritic cells to control autoimmune inflammation (2011) J Immunol, 187, pp. 4018-4030Sun, Y., Chin, Y.E., Weisiger, E., Cutting edge: Negative regulation of dendritic cells through acetylation of the nonhistone protein STAT-3 (2009) J Immunol, 182, pp. 5899-5903Enioutina, E.Y., Bareyan, D., Daynes, R.A., Vitamin D3-mediated alterations to myeloid dendritic cell trafficking in vivo expand the scope of their antigen presenting properties (2007) Vaccine, 25, pp. 1236-1249Pallotta, M.T., Orabona, C., Volpi, C., Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells (2011) Nat Immunol, 12, pp. 870-878Steinbrink, K., Wolfl, M., Jonuleit, H., Knop, J., Enk, A.H., Induction of tolerance by IL-10-treated dendritic cells (1997) J Immunol, 159, pp. 4772-4780Chen, W., IDO: More than an enzyme (2011) Nat Immunol, 12, pp. 809-811Smolders, J., Peelen, E., Thewissen, M., The relevance of vitamin D receptor gene polymorphisms for vitamin D research in multiple sclerosis (2009) Autoimmun Rev, 8, pp. 621-62

Gout, allopurinol intake and clinical outcomes in the hospitalized multimorbid elderly.

Increased serum uric acid has been considered a cardiovascular risk factor but no study has assessed its relation with hospital mortality or length of stay. On the basis of data obtained from a prospective registry, the prevalence of gout/hyperuricemia and its association with these and other clinical parameters was evaluated in an Italian cohort of elderly patients acutely admitted to internal medicine or geriatric wards

Human immunodeficiency virus continuum of care in 11 european union countries at the end of 2016 overall and by key population: Have we made progress?

Background. High uptake of antiretroviral treatment (ART) is essential to reduce human immunodeficiency virus (HIV) transmission and related mortality; however, gaps in care exist. We aimed to construct the continuum of HIV care (CoC) in 2016 in 11 European Union (EU) countries, overall and by key population and sex. To estimate progress toward the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 target, we compared 2016 to 2013 estimates for the same countries, representing 73% of the population in the region. Methods. A CoC with the following 4 stages was constructed: number of people living with HIV (PLHIV); proportion of PLHIV diagnosed; proportion of those diagnosed who ever initiated ART; and proportion of those ever treated who achieved viral suppression at their last visit. Results. We estimated that 87% of PLHIV were diagnosed; 92% of those diagnosed had ever initiated ART; and 91% of those ever on ART, or 73% of all PLHIV, were virally suppressed. Corresponding figures for men having sex with men were: 86%, 93%, 93%, 74%; for people who inject drugs: 94%, 88%, 85%, 70%; and for heterosexuals: 86%, 92%, 91%, 72%. The proportion suppressed of all PLHIV ranged from 59% to 86% across countries. Conclusions. The EU is close to the 90-90-90 target and achieved the UNAIDS target of 73% of all PLHIV virally suppressed, significant progress since 2013 when 60% of all PLHIV were virally suppressed. Strengthening of testing programs and treatment support, along with prevention interventions, are needed to achieve HIV epidemic control