HLA-haploidentical hematopoietic stem cells transplantation with regulatory and conventional T-cell adoptive immunotherapy in pediatric patients with very high-risk acute leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is still needed for many children with very high-risk acute leukemia. An HLA-haploidentical family donor is a suitable option for those without an HLA-matched donor. Here we present outcomes of a novel HLA-haploidentical HSCT (haplo-HSCT) strategy with adoptive immunotherapy with thymic-derived CD4+CD25+ FoxP3+ regulatory T cells (Tregs) and conventional T cells (Tcons) performed between January 2017 and July 2021 in 20 children with high-risk leukemia. Median age was 14.5 years (range, 4-21), 15 had acute lymphoblastic leukemia, 5 acute myeloid leukemia. The conditioning regimen included total body irradiation (TBI), thiotepa, fludarabine, cyclophosphamide. Grafts contained a megadose of CD34+ cells (mean 12.4 × 106/Kg), Tregs (2 × 106/Kg) and Tcons (0.5-1 × 106/Kg). All patients achieved primary, sustained full-donor engraftment. Only one patient relapsed (5%). The incidence of non-relapse mortality was 15% (3/20 patients). Five/20 patients developed ≥ grade 2 acute Graft versus Host Disease (aGvHD). It resolved in 4 who are alive and disease-free; 1 patient developed chronic GvHD (cGvHD). The probability of GRFS was 60 ± 0.5% (95% CI: 2.1-4.2) (Fig. 6), CRFS was 79 ± 0.9% (95% CI: 3.2-4.9) as 16/20 patients are alive and leukemia-free. The median follow-up was 2.1 years (range 0.5 months-5.1 years). This innovative approach was associated with very promising outcomes of HSCT strategy in pediatric patients.

Adrenocorticotropic hormone influences the development of adaptive changes in dopamine autoreceptors induced by chronic administration of desipramine.

The influence of adrenocorticotropic hormone (ACTH) in the adaptive changes on central dopamine (DA) autoreceptors following chronic administration of desipramine (DMI) has been examined in rats. Dopamine had an inhibitory effect on basal and K(+)-induced release of [3H]DA from slices of striatum and n. accumbens of rats treated chronically (10 days) with ACTH (50 IU/kg, s.c.), DMI (10 mg/kg, i.p.) or the combination of ACTH and DMI. In slices of n. accumbens, but not in slices of striatum of rats exposed to the combined treatment of ACTH and DMI, a significant decrease in the inhibitory effect of exogenous DA on stimulated release of [3H]DA was observed. Chronic administration of ACTH or DMI alone had no effect. The effect of the combined treatment with both agents, on the reactivity of these DA receptors was evaluated by means of apomorphine-induced hypoactivity. The administration of ACTH and DMI (5 mg/kg, i.p.) reduced the hypoactivity induced by apomorphine, as compared to hypoactivity in rats treated with ACTH or DMI alone. Experiments with ACTH4-10 revealed that the peptide modified biochemical and behavioural parameters of dopaminergic function, which may implicate a direct action of the peptide on the brain, rather than on the release of adrenal hormones. These findings suggest that ACTH accelerates the onset of DMI-induced adaptive changes on dopamine in the mesolimbic area. However, because the effect of ACTH4-10 on release of adrenocortical hormone was not investigated, the possibility cannot be disregarded that the effect of the peptide was secondary to an enhancement of release of adrenal hormone.