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Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers
No full textWe defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 + T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 + immune cells.
Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response
HNF4α, SP1 and c-myc are master regulators of CNS autoimmunity doi.org/10.1016/j.jaut.2023.103053
No full textData related to manuscript "HNF4α, SP1 and c-myc are master regulators of CNS autoimmunity" by Colombo et al, J Autoimmun. 2023 Jul;138:103053. doi: 10.1016/j.jaut.2023.103053
Deciphering the impact of letermovir on the immune-reconstitution of protective Cytomegalovirus-specific T-cells in allogeneic hematopoietic stem cell transplantation in post-transplant cyclophosphamide era
No full textThe introduction of letermovir (LTV) in prophylaxis after allogeneic-hematopoietic stem cell transplantation (allo-HSCT) has reduced the incidence of Cytomegalovirus (CMV) clinically relevant reactivations (CRE), but these events increase after LTV cessation. CMV-specific T cells protect the patients against CRE, but the mechanisms stimulating their emergence during or immediately after LTV treatment need to be further explored, especially in the setting of post-transplant cyclophosphamide (PT-Cy).
In this study, we analyzed 42 CMV-seropositive adult patients with hematological malignancies undergoing allo-HSCT with PT-Cy and calcineurin inhibitor (CNI)-free GvHD prophylaxis in a single-center observational study. Fifteen patients received LTV as prophylaxis in the first 100 days after transplant. CMV-specific CD8+ T cells were quantified by flow cytometry using Dextramer® CMV-Kit (IVD, Immudex) in PBMC frozen 90 (D90) and 180 (D180) days after allo-HSCT, and protective anti-viral immunity was defined based on the threshold that we had previously identified of 0.5 CMV-specific cells/ul.
Our findings reinforce the protective role of LTV against clinically relevant CMV-CRE and confirm that LTV prophylaxis is associated with a delayed reconstitution of CMV-specific CD8⁺ T cells compared to no-LTV patients. Importantly, our data underscore the pivotal role of antigen exposure—even transient and at low levels, such as during CMV blips—in promoting the expansion of protective levels of CMV-specific T lymphocytes. This suggests that minimal antigenic stimulation is sufficient to boost protective CMV-specific immune responses in the context of ongoing reconstitution
Specific types of male infertility are correlated with T cell exhaustion or senescence signatures
No full textInfertility affects almost 15–20% of couples of reproductive age in Western countries, and a pure male factor is responsible for about half of these cases. Despite infertile men show a poorer general health status compared to age-matched fertile men, a comprehensive understanding of the association between infertility and the overall impoverishment of men's health was still lacking.
In the manuscript “Specific types of male infertility are correlated with T cell exhaustion or senescence signatures" (doi.org/10.1038/s41467-025-56193-2), we investigated the immune system of primary infertile men. We showed that both the semen and blood of these subjects exhibit a pro-inflammatory status resembling the one found in elderly men, suggesting that infertility could be linked to early aging of the immune system.
The datasets loaded contain all the clinical and immunological data supporting our conclusions and that have been used to build the main and supplementary figures/tables of the manuscript. An additional file (raw_data_description) contains the main guidelines to correctly associate the raw data with the corresponding figure/table in the manuscript
Association between NTRK2 Polymorphisms, Hippocampal Volumes and Treatment Resistance in Major Depressive Disorder
No full textDespite the increasing availability of antidepressant drugs, a high rate of patients with major depression (MDD) does not respond to pharmacological treatments. Brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling is thought to influence antidepressant efficacy and hippocampal volumes, robust predictors of treatment resistance. We therefore hypothesized the possible role of BDNF and neurotrophic receptor tyrosine kinase 2 (NTRK2)-related polymorphisms in affecting both hippocampal volumes and treatment resistance in MDD. A total of 121 MDD inpatients underwent 3T structural MRI scanning and blood sampling to obtain genotype information. General linear models and binary logistic regressions were employed to test the effect of genetic variations related to BDNF and NTRK2 on bilateral hippocampal volumes and treatment resistance, respectively. Finally, the possible mediating role of hippocampal volumes on the relationship between genetic markers and treatment response was investigated. A significant association between one NTRK2 polymorphism with hippocampal volumes and antidepressant response was found, with significant indirect effects. Our results highlight a possible mechanistic explanation of antidepressant action, possibly contributing to the understanding of MDD pathophysiology
In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation
No full textDespite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8+ T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4+ T cell help. IFNα and IL-12 produced by armed macrophages reprogram antigen presenting cells and rewire cellular interactions, rescuing tumor reactive T cell functions. In vivo armed macrophages trigger anti-tumor immunity in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases.
Data availability: The MERFISH, single-cell RNA sequencing and bulk RNA sequencing data have been deposited in the GEO repository under the accession number GSE273615. Additionally, the WES data have been uploaded to the ENA portal with the accession number PRJEB78386.
Code availability: Code is available at the following link: http://www.bioinfotiget.it/gitlab/custom/notaro_mouse_lm_2025
Human iPSC-derived neural stem cells displaying radial glia signature exhibit long-term safety in mice
No full textThe dataset includes the raw data of graphs shown in figures 1, 2, 3, 5, 6, and 7 and in supplementary figures 1, 2, 3, 4, 5, 7, and 8 of the paper: Human iPSC-derived neural stem cells displaying radial glia signature exhibit long-term safety in mice. Luciani M, Garsia C, Beretta S, Cifola I, Peano C, Merelli I, Petiti L, Miccio A, Meneghini V, Gritti A. Nat Commun. 2024 Nov 1;15(1):9433. doi: 10.1038/s41467-024-53613-7. PMID: 39487141
The bulk RNA-seq, SREBF1-deficient RNA-seq, and ChIP-seq data generated in this study have been deposited at GEO under accession number GSE239446. The single-cell RNA-seq data generated in this study have been deposited at GEO under accession number GSE238206. The processed RNA-seq, ChIP-seq, and scRNA-seq data (list of DEGs and GO terms) are available in Supplementary Data 1-4 files.
Human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NSCs) hold promise for treating neurodegenerative and demyelinating disorders. However, comprehensive studies on their identity and safety remain limited. In this study, we demonstrate that hiPSC-NSCs adopt a radial glia-associated signature, sharing key epigenetic and transcriptional characteristics with human fetal neural stem cells (hfNSCs) while exhibiting divergent profiles from glioblastoma stem cells. Long-term transplantation studies in mice showed robust and stable engraftment of hiPSC-NSCs, with predominant differentiation into glial cells and no evidence of tumor formation. Additionally, we identified the Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1) as a regulator of astroglial differentiation in hiPSC-NSCs. These findings provide valuable transcriptional and epigenetic reference datasets to prospectively define the maturation stage of NSCs derived from different hiPSC sources and demonstrate the long-term safety of hiPSC-NSCs, reinforcing their potential as a viable alternative to hfNSCs for clinical applications
A machine learning pipeline for efficient differentiation between bipolar and major depressive disorder based on multimodal structural neuroimaging
No full textDue to the overlapping depressive symptomatology with major depressive disorder (MDD), 60% of patients with bipolar disorder (BD) are initially misdiagnosed, calling for the definition of reliable biomarkers that can support the diagnostic process. Here, we optimized a machine learning pipeline for the differentiation between depressed BD and MDD patients based on multimodal structural neuroimaging features. Diffusion tensor imaging (DTI) and T1-weighted magnetic resonance imaging (MRI) data were acquired for 282 depressed BD (n = 180) and MDD (n = 102) patients. Images were preprocessed to obtain axial (AD), radial (RD), mean (MD) diffusivity, fractional anisotropy (FA), and voxel-based morphometry (VBM) maps. Each feature was entered separately into a 5-fold nested cross-validated predictive pipeline differentiating between BD and MDD patients, comprising: confound regression for nuisance variables removal, feature standardization, principal component analysis for feature reduction, and an elastic-net penalized regression. The DTI-based models reached accuracies ranging from 75% to 78%, whereas the VBM model reached 61% of accuracy. All the models were significantly different from a null model distribution at a 5000-permutation test. A 5000 bootstrap procedure revealed that widespread differences drove the classification, with BD patients associated to overall higher values of AD and FA, and grey matter volumes. Our results suggest that structural neuroimaging, in particular white matter microstructure and grey matter volumes, may be able to differentiate between MDD and BD patients with good predictive accuracy, being significantly higher than chance-level
Long-term effect of childhood trauma: Role of inflammation and white matter in mood disorders
No full textBipolar disorder (BD) and major depressive disorder (MDD) are severe psychiatric illnesses that share among their environmental risk factors the exposure to adverse childhood experiences (ACE). Exposure to ACE has been associated with long-term changes in brain structure and the immune response. In the lasts decades, brain abnormalities including alterations of white matter (WM) microstructure and higher levels of peripheral immune/inflammatory markers have been reported in BD and MDD and an association between inflammation and WM microstructure has been shown. However, differences in these measures have been reported by comparing the two diagnostic groups. The aim of the present study was to investigate the interplay between ACE, inflammation, and WM in BD and MDD. We hypothesize that inflammation will mediate the association between ACE and WM and that this will be different in the two groups. A sample of 200 patients (100 BD, 100 MDD) underwent 3T MRI scan and ACE assessment through Childhood Trauma Questionnaire. A subgroup of 130 patients (75 MDD and 55 BD) underwent blood sampling for the assessment of immune/inflammatory markers. We observed that ACE associated with higher peripheral levels of IL-2, IL-17, bFGF, IFN-γ, TNF-α, CCL3, CCL4, CCL5, and PDGFBB only in the BD group. Further, higher levels of CCL3 and IL-2 associated with lower FA in BD. ACE were found to differently affect WM microstructure in the two diagnostic groups and to be negatively associated with FA and AD in BD patients. Mediation analyses showed a significant indirect effect of ACE on WM microstructure mediated by IL-2. Our findings suggest that inflammation may mediating the detrimental effect of early experiences on brain structure and different mechanism underlying brain alterations in BD and MDD
Reprogramming liver metastasis-associated macrophages towards an anti-tumoral phenotype through enforced miR-342 expression
No full textUpon metastatic seeding in the liver, liver macrophages, including Kupffer cells, acquire a transcriptional profile typical of tumor-associated macrophages (TAMs), which support tumor progression. MicroRNAs (miRNAs) fine-tune TAM pro-tumoral functions, making their modulation a promising strategy for macrophage reprogramming into an anti-tumoral phenotype. Here, we analyze the transcriptomic profiles of liver and splenic macrophages, identifying miR-342-3p as a key regulator of liver macrophage function. miR-342-3p is highly active in healthy liver macrophages but significantly downregulated in colorectal cancer liver metastases (CRLMs). Lentiviral vector-engineered liver macrophages enforcing miR-342-3p expression acquire a pro-inflammatory phenotype and reduce CRLM growth. We identify Slc7a11, a cysteine-glutamate antiporter linked to pro-tumoral activity, as a direct miR-342-3p target, which may be at least partially responsible for TAM phenotypic reprogramming. Our findings highlight the potential of in vivo miRNA modulation as a therapeutic strategy for TAM reprogramming, offering an approach to enhance cancer immunotherapy.
Data and code availability: Next-generation sequencing data are deposited at the Gene Expression Omnibus (GEO) with the following accession numbers: GEO: GSE274043 (scRNA-seq), GSE274044 (RNA-seq on iKCs), GSE274045 (small RNA-seq on splenic and hepatic cell populations), and GSE274046 (bulk RNA-seq on splenic and hepatic cell populations). The code is available at GitLab: http://www.bioinfotiget.it/gitlab/custom/Bresesti_Cell_Reports_2025