DISCUSSION
thalassemia, memory CD4Immune dysfunctions, SARS‐CoV‐2 infection, β‐Thalassemia
CORONAVIRUS DISEASE 2019, APC, CORONAVIRUS, HEMOGLOBINOPATHIES, PROLIFERATIVE, THALASSEMIA, SEVERE ACUTE RESPIRATORY SYNDROME, INFLUENZA
The main results of the present study are that treatment of β‐Thalassemia patients with Sirolimus has a positive impact on the biological activity of memory CD4Immune dysfunctions characterizing thalassemia patients include changes in lymphocyte subsets, such as the accumulation of suppressor T cells and the reduced proliferative capacity and numbers of T helper cells, as well as the defective activity of natural killer (NK) cells. Similarly, an altered humoral immunity has been shown in patients with β‐Thalassemia.In this context, our results are in line with several observations reporting that mTOR inhibitors (such as Sirolimus) are Immunomodulatory molecules of great interest in the context of vaccination, since they might have an effect on the cellular memory response, possibly enhancing long‐term effects of vaccines. Accordingly, Sirolimus were found by Mannick et al. to improve responses to influenza vaccination in adults, with benefits possibly persisting for a year after treatment.This is an important issue of the vaccination campaign against the severe acute respiratory syndrome coronavirus (SARS‐CoV‐2), causing the dramatic COVID‐19 (coronavirus disease 2019) pandemic.In this context, Netti et al.Our present study confirms the possible beneficial role of the mTOR inhibitor Sirolimus on the biological activity of memory T cells in β‐Thalassemia patients. The results obtained demonstrate that Sirolimus preserves and enhances the number and activity of epitope‐specific CD4Although the levels of autophagy measured in CD4 and CD8 memory subpopulations tended to rise, it remains unclear if Sirolimus dosage adopted in this study is sufficient to promote autophagy in T cells and if this is directly related to the biological effect of enhancing memory T‐cell releasing IFN‐γ following stimulation; future experiments might consider using Chloroquine or Bafilomycin in order to better detect autophagic flux,Our data do not clarify mitochondrial overall activity, metabolism and possible activation of mitophagy in CD4Of interest is also the decrease of IL‐13 (Figure Finally, a remarkable decrease of G‐CSF was observed (Figure Our data do not clarify whether the effect of Sirolimus was mediated directly on memory T cells or indirectly on APC. This cannot be in theory excluded, as it is known that autophagy processes regulate peptide presentation in professional antigen‐presenting cells, which mediate thymocyte selection.In any case, and whatever being the mechanism of action, the beneficial effect of Sirolimus treatment on COVID‐19 vaccination might be of great interest for managing β‐Thalassemia, as an increased mortality risk from COVID‐19 was observed in Italian patients affected by hemoglobinopathies, including β‐Thalassemia.It must be noted that in addition to possible boosting effects on vaccination efficacy/duration, mTOR inhibition is under investigation also as a new therapeutic option in the management of SARS‐CoV‐2 infection.