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.
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.
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.
- 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)