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Immunoregulation and Inflammation

MEMBERS

  • Marcelo Hill MD, PhD (Head)
  • Mercedes Segovia (Post-doc)
  • Maite Duhalde (Post-doc)
  • Sofía Russo (Master)
  • Mª Eugenia Schroeder (Master)
  • Florencia Rammauro (Master)
  • Matías Jeldres (stage)
  • Mariana Seija (stage)

MAIN EQUIPMENT

SERVICES

RESEARCH

Dysregulation of immune responses leads to chronic inflammatory disorders collectively called immune-mediated inflammatory diseases (IMIDs). More than 80 clinically distinct diseases have been identified within this category, including classical autoimmune diseases, graft rejection and graft-versus host disease, asthma and atopy, psoriasis, immunodeficiencies, and chronic inflammatory diseases such as inflammatory nephropathies and atherosclerosis (Baeten 2009). IMIDs affect approximately 10 percent of the population and, for reasons that are not yet clear, the prevalence of these diseases appears to be rising. Cancer is another pathophysiological scenario where inflammation is part of the natural history of the disease. Furthermore, the biological basis of the effect obtained with pharmacological agents such as hydroxychloroquine (HCQ), currently used to impair immune-mediated damage, are not fully understood. Basic research is therefore needed to better characterize immunoregulatory mechanisms and new targets to control inflammation.

We have recently described new physiologic mechanisms which can control immune-mediated damage (Guillonneau et al. 2007; Hill et al. 2007a; Hill et al. 2007b; Hill et al. 2011). This knowledge can help to understand the natural history of IMIDS at the cellular and molecular level. Moreover, characterization of novel immunoregulatory mechanisms is an important issue to rationalize immunointerventional strategies (Hill et al. 2011) as well as to understand the pharmacodynamics of currently used anti-inflammatory drugs.

The laboratory of immunoregulation and inflammation has been established at the IP Montevideo in October 2013. Our laboratory studies cellular and molecular mechanisms which can control inflammation and adaptive immune responses. We are focused on the biology of dendritic cells (DCs). This is a particular subset of leukocytes which can trigger effector but also regulatory immune responses.

We are interested in the study of inflammasomes activation. Inflammasomes are cytoplasmic multi-protein complexes composed of a sensor protein (NOD-like) and an adaptor (ASC) which, once assembled, are able to activate pro-caspase-1 into caspase-1. Some of the targets of activated caspase-1 are pro-IL-1beta and pro-IL-18. Proteolytical process of these precursors by caspase-1 transforms them into active cytokines with a powerful pro-inflammatory action. In the last years, the cytoplasmic ionic composition has emerged as a one of the most studied mechanisms by which inflammasome activation is regulated (Latz et al. 2013). Indeed, characterizing new ion channel will certainly shed light on original mechanisms of inflamasomme activation. This context gives the main rational bases of our lines of investigation.

Research lines

  • Study of the impact of new ion channels on the activation of inflammasomes.
  • Analysis of novel ion channels in cancer patients and in tumoral experimental models.
  • Characterization of novel anti-inflammatory mechanisms triggered by hydroxychloroquine through the inhibition of ion channels.
  • Study of the expression of new ion channels in autoimmune patients.
  1. Baeten, D. (2009). “Memorandum of understanding for the implementation of a European Concerted Research Action designates as COST Action BM0907: European Network for Translational Immunology Research and Education (ENTIRE): From Immunomonitoring to personalized immunotherapy.”
  2. Guillonneau, C., M. Hill, F. X. Hubert, E. Chiffoleau, C. Hervé, X.-L. Li, M. Heslan, C. Usal, L. Tesson, S. Ménoret, A. Saoudi, B. Le Mauff, R. Josien, M. C. Cuturi and I. Anegon (2007). “CD40Ig treatment results in allograft acceptance mediated by CD8+CD45RClow T cells, IFN-gamma and indoleamine 2,3-dioxygenase.” J Clin Invest117(4): 1096-106.
  3. Hill, M., S. Tanguy-Royer, P. J. Royer, C. Chauveau, K. Asghar, L. Tesson, F. Lavainne, S. Rémy, R. Brion, F. X. Hubert, M. Heslan, M. Rimbert, L. Berthelot, J. Moffett, R. Josien, M. Gregoire and I. Anegon (2007a). “IDO expands human CD4+CD25high regulatory T cells by promoting maturation of LPS-treated dendritic cells.” Eur J Immunol.37(11): 3054-62.
  4. Hill, M., R. Zagani, C. Voisine, C. Usal and I. Anegon (2007b). “Nitric oxide and indoleamine 2,3-dioxygenase mediate CTLA4Ig-induced survival of heart allografts in rats.” Transplantation84(8): 1060-3.
  5. Hill, M., P. Thebault, M. Segovia, C. Louvet, G. Beriou, G. Tilly, E. Merieau, I. Anegon, E. Chiffoleau and M. C. Cuturi (2011). “Cell therapy with autologous tolerogenic dendritic cells induces allograft tolerance through interferon-gamma and epstein-barr virus-induced gene 3.” Am J Transplant11(10): 2036-45.
  6. Latz, E., TS. Xiao and A. Stutz. (2013). “Activation and regulation of the inflammasomes”. Nat Rev Immunol 13: 397-411

EDUCATION-COURSES

GRANTS

  1. CABBIO 2015-2017
  2. FMV 2014-2016

PUBLICATIONS

  1. Segovia M, Louvet C, Charnet P, Savina A, Tilly G, Gautreau L, Carretero-Iglesia L, Beriou G, Cebrian I, Cens T, Hepburn L, Chiffoleau E, Floto RA, Anegon I, Amigorena S, Hill M, Cuturi MC. Autologous dendritic cells prolong allograft survival through Tmem176b-dependent antigen cross-presentation (2014) American Journal of Transplantation, 14 (5), pp. 1021-1031. – IF: 6.1
  2. Drujont L, Carretero-Iglesia L, Bouchet-Delbos L, Beriou G, Merieau E, Hill M, Delneste Y, Cuturi MC, Louvet C. Evaluation of the therapeutic potential of bone Marrow-Derived Myeloid Suppressor Cell (MDSC) adoptive transfer in mouse models of autoimmunity and allograft rejection (2014) PLoS ONE, 9 (6), art. N° e100013. – IF: 3.534
  3. Moreau A, Vandamme C, Segovia M, Devaux M, Guilbaud M, Tilly G, Jaulin N, Le Duff J, Cherel Y, Deschamps JY, Anegon I, Moullier P, Cuturi  MC and Adjali O. Generation and in vivo evaluation of IL10-treated dendritic cells in a nonhuman primate model of AAV-based gene transfer Citation: Molecular Therapy — Methods & Clinical Development (2014) 1, 14028; doi:10.1038/mtm.2014.28  © 2014 The American Society of Gene & Cell Therapy All rights reserved 2329-0501/14. – IF: —
  4. Baas MC, Kuhn C, Valette F, Mangez C, Duarte MS, Hill M, Besançon A, Chatenoud L, Cuturi MC, You S. Combining autologous dendritic cell therapy with CD3 antibodies promotes regulatory T cells and permanent Islet allograft acceptance. Journal of Immunology Volume 193, Issue 9, 1 November 2014, Pages 4696-4703. – IF: 5.362.

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