Enrico Velardi, PhD

Research Fellow
Pictured: Enrico Velardi
Lab Phone:
646-888-2317
Education:
University of Perugia, Perugia, Italy

My research is currently focused in understanding the biology underlying the decline and recovery of the thymus and bone marrow after immune insults, and use this knowledge to individuate therapeutic targets for the regeneration of the immune system in immunocompromised patients.

Optimal recovery of immune function is a critical process in several clinical situations such as after cytoreductive chemo- or radiation therapy, infection, shock, as well as after radiation injury. Prolonged immune suppression has consequences at multiple levels including increased opportunistic infections, malignant relapse, morbidity and mortality. Therefore, development of strategies to improve the regeneration of immune system and reconstitution of the peripheral T cell pool represents a significant clinical challenge with the potential to improve overall outcome in immunocompromised recipients.

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The thymus, which is primarily responsible for generating T cells with a diverse T cell receptor (TCR) repertoire, undergoes a severe involution with age.This decline in thymic function has been in part attributed to the increase in sex steroids after puberty, and their removal promotes thymic regeneration. We have recently show that one of the mechanisms by which sex steroids regulate thymic function is through direct modulation of the Notch ligand Delta-like 4 (Dll4), a critical gene involved in T cell commitment and differentiation (Velardi et al. Journal of  Experimental Medicine 2014 Nov 17;211(12):2341-9). We found that administration of testosterone decreased the expression of Dll4 specifically in cortical thymic epithelial cells (cTECs).Using a computational approach, and subsequently validated by ChIP studies, we found that the androgen receptor (AR) could directly bind and negatively regulate the promoter of Dll4. Consistent with this, sex steroid ablation (SSA), using a novel class of luteinizing hormone releasing hormone receptor antagonists (LHRH-Ant), promoted upregulation of Dll4 in cTECs and its downstream target genes Hes1, Ptcra and CD25 in double-negative 3 thymocytes. Importantly, we also found that LHRH-Ant treatment bypassed the surge in sex steroids caused by LHRH-R agonists - the gold standard for clinical SSA – thereby facilitating more rapid promotion of thymopoiesis. Using clinically relevant mouse models of immune injury, we found that the LHRH-Ant promoted faster thymic regeneration after total body irradiation resulting in faster peripheral T cell reconstitution and enhanced viral clearance.

Awards

  • ASH Abstract Achievement Award (55th ASH Annual Meeting), New Orleans, LA (2014)
  • American Society for Blood and Marrow Transplantation New Investigator Award (2013)
  • Italian Foundation for Cancer Research Award for Abroad Research (2011)
  • Italian Society of Pharmacology Award for Abroad Research (2011)
Publications by Enrico Velardi
  1. Velardi E, Tsai JJ, Holland AM, Wertheimer T, Yu VW, Zakrzewski JL, Tuckett AZ, Singer NV, West ML, Smith OM, Young LF, Kreines FM, Levy ER, Boyd RL, Scadden DT, Dudakov JA, van den Brink MR. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J Exp Med. 2014 Nov 17;211(12):2341-9. doi: 10.1084/jem.20131289. Epub 2014 Oct 20.
  2. Ferrando-Martínez S, Ruiz-Mateos E, Dudakov JA, Velardi E, Grillari J, Kreil DP, Muñoz-Fernandez MA, van den Brink MR, Leal M. WNT Signaling Suppression in the Senescent Human Thymus. WNT Signaling Suppression in the Senescent Human Thymus. J Gerontol A Biol Sci Med Sci. 2014 Mar 30.
  3. Velardi E, Dudakov JA, van den Brink MR. Clinical strategies to enhance thymic recovery after allogeneic hematopoietic stem cell transplantation. Immunol Lett. 2013 Sep-Oct;155(1-2):31-5. doi: 10.1016/j.imlet.2013.09.016. Epub 2013 Oct 8.
  4. Ghosh A, Dogan Y, Moroz M, Holland AM, Yim NL, Rao UK, Young LF, Tannenbaum D, Masih D, Velardi E, Tsai JJ, Jenq RR, Penack O, Hanash AM, Smith OM, Piersanti K, Lezcano C, Murphy GF, Liu C, Palomba ML, Sauer MG, Sadelain M, Ponomarev V, van den Brink MR. Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity. J Clin Invest. 2013 Jun;123(6):2654-62. doi: 10.1172/JCI66301. Epub 2013 May 15.
  5. Tsai JJ, Dudakov JA, Takahashi K, Shieh JH, Velardi E, Holland AM, Singer NV, West ML, Smith OM, Young LF, Shono Y, Ghosh A, Hanash AM, Tran HT, Moore MA, van den Brink MR. Nrf2 regulates haematopoietic stem cell function. Nat Cell Biol. 2013 Mar;15(3):309-16. doi: 10.1038/ncb2699. Epub 2013 Feb 24.