Enrico Velardi, PhD

Research Associate

Lab Phone



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 hematopoietic system in immunocompromised patients.

Optimal recovery of hematopoietic 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 hematopoietic system and reconstitution of the peripheral T cell pool represents a significant clinical challenge with the potential to improve overall outcome in immunocompromised recipients.

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.


  • Immunology and Microbial Pathogenesis (IMP) Scientific Retreat Publication Award (2015)
  • AAI Trainee Abstract Award (The American Association of Immunologists Annual Meeting –  New Orleans, LA) (2015)
  • 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)


  1. Argyropoulos KV, Vogel R, Ziegler C, Altan-Bonnet G, Velardi E, Calafiore M, Dogan A, Arcila M, Patel M, Knapp K, Mallek C, Hunter ZR, Treon SP, van den Brink MR, Palomba ML. 2016. Clonal B cells in Waldenstrom’s macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling. Leukemia

  2. Velardi E, Dudakov JA, van den Brink MR. 2015. Sex steroid ablation: an immunoregenerative strategy for immunocompromised patients. Bone Marrow Transplant 50 Suppl 2: S77-81

  3. van den Brink MR, Velardi E, Perales MA. 2015. Immune reconstitution following stem cell transplantation. Hematology Am Soc Hematol Educ Program 2015: 215-9

  4. Lindemans CA, Calafiore M, Mertelsmann AM, O’Connor MH, Dudakov JA, Jenq RR, Velardi E, Young LF, Smith OM, Lawrence G, Ivanov JA, Fu YY, Takashima S, Hua G, Martin ML, O’Rourke KP, Lo YH, Mokry M, Romera-Hernandez M, Cupedo T, Dow LE, Nieuwenhuis EE, Shroyer NF, Liu C, Kolesnick R, van den Brink MR, Hanash AM. 2015. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528: 560-4

  5. Ferrando-Martinez S, Ruiz-Mateos E, Dudakov JA, Velardi E, Grillari J, Kreil DP, Munoz-Fernandez MA, van den Brink MR, Leal M. 2015. WNT signaling suppression in the senescent human thymus. J Gerontol A Biol Sci Med Sci 70: 273-81

  6. 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. 2014. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J Exp Med 211: 2341-9

  7. Velardi E, Dudakov JA, van den Brink MR. 2013. Clinical strategies to enhance thymic recovery after allogeneic hematopoietic stem cell transplantation. Immunol Lett 155: 31-5

  8. 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. 2013. Nrf2 regulates haematopoietic stem cell function. Nat Cell Biol 15: 309-16

  9. 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. 2013. Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity. J Clin Invest 123: 2654-62

  10. Hanash AM, Dudakov JA, Hua G, O’Connor MH, Young LF, Singer NV, West ML, Jenq RR, Holland AM, Kappel LW, Ghosh A, Tsai JJ, Rao UK, Yim NL, Smith OM, Velardi E, Hawryluk EB, Murphy GF, Liu C, Fouser LA, Kolesnick R, Blazar BR, van den Brink MR. 2012. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37: 339-50