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"Lecis, Alessandro"
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I am not Little Red Riding Hood!
A little girl goes into the woods to collect snow and meets a magical bear who has an important lesson to teach her.
Book
Immune-tolerance to human iPS-derived neural progenitors xenografted into the immature cerebellum is overridden by species-specific differences in differentiation timing
We xeno-transplanted human neural precursor cells derived from induced pluripotent stem cells into the cerebellum and brainstem of mice and rats during prenatal development or the first postnatal week. The transplants survived and started to differentiate up to 1 month after birth when they were rejected by both species. Extended survival and differentiation of the same cells were obtained only when they were transplanted in NOD-SCID mice. Transplants of human neural precursor cells mixed with the same cells after partial in vitro differentiation or with a cellular extract obtained from adult rat cerebellum increased survival of the xeno-graft beyond one month. These findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts induction of immune-tolerance to human antigens expressed before completion of maturation of the immune system. With further maturation the transplanted neural precursors expressed more mature antigens before the graft were rejected. Supplementation of the immature cells suspensions with more mature antigens may help to induce immune-tolerance for those antigens expressed only later by the engrafted cells.
Journal Article
DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients
Ataxia Telangiectasia (A-T) is neurodegenerative syndrome caused by inherited mutations inactivating the ATM kinase, a master regulator of the DNA damage response (DDR). What makes neurons vulnerable to ATM loss remains unclear. In this study we assessed on human iPSC-derived neurons whether the abnormal accumulation of DNA-Topoisomerase 1 adducts (Top1ccs) found in A-T impairs transcription elongation, thus favoring neurodegeneration. Furthermore, whether neuronal activity-induced immediate early genes (IEGs), a process involving the formation of DNA breaks, is affected by ATM deficiency. We found that Top1cc trapping by CPT induces an ATM-dependent DDR as well as an ATM-independent induction of IEGs and repression especially of long genes. As revealed by nascent RNA sequencing, transcriptional elongation and recovery were found to proceed with the same rate, irrespective of gene length and ATM status. Neuronal activity induced by glutamate receptors stimulation, or membrane depolarization with KCl, triggered a DDR and expression of IEGs, the latter independent of ATM. In unperturbed A-T neurons a set of genes (FN1, DCN, RASGRF1, FZD1, EOMES, SHH, NR2E1) implicated in the development, maintenance and physiology of central nervous system was specifically downregulated, underscoring their potential involvement in the neurodegenerative process in A-T patients.
Journal Article
Immunomodulation Therapies for Atherosclerosis: The Past, the Present, and the Future
Atherosclerotic cardiovascular disease is the most common cause of morbidity and death worldwide. Recent studies have demonstrated that this chronic inflammatory disease of the arterial wall can be controlled through the modulation of immune system activity. Many patients with cardiovascular disease remain at elevated risk of recurrent events despite receiving current, state-of-the-art preventive medical treatment. Much of this residual risk is attributed to inflammation. Therefore, finding new treatment strategies for this category of patients became of common interest. This review will discuss the experimental and clinical data supporting the possibility of developing immune-based therapies for lowering cardiovascular risk, explicitly focusing on vaccination strategies.
Journal Article
Notulae to the Italian alien vascular flora: 13
In this contribution, new data concerning the distribution of vascular flora alien to Italy are presented. It includes new records, confirmations, exclusions, and status changes for Italy or for Italian administrative regions. Nomenclatural and distribution updates published elsewhere are provided as Suppl. material 1.
Journal Article
ANTIGEN-SPECIFIC CD8+ T-CELLS ARE INVOLVED IN HUMAN CAROTID ATHEROSCLEROTIC PLAQUES DESTABILIZATION
Immunization of ApoE-/- mice expressing human HLA-A 02:01 with p210, an apoB100-derived peptide, reduces atherosclerotic plaque development by inducing a p210-specific CD8+ T cell population. Studying Class-I MHC/CD8+ T cell signaling offers a promising approach to understanding the mechanism behind the athero-protective effects of p210 immunization. We aimed to identify a p210-specific CD8+ T cell population in human carotid atherosclerotic plaques from blood-positive HLA-A 02:01 patients undergoing surgical carotid endarterectomy (CEA). The study included 22 consecutive patients who were HLA-A 02:01 (+) out of 49 enrolled (reflecting an estimated prevalence of about 30% HLA-A02:01(+) in the Caucasian population). Immunohistochemistry staining used a PE-marked A 02:01–KTTKQSFDL Pentamer on fixed endarterectomy plaques. Both HLA-A 02:01 (+) and (-) patient plaques were used, with the latter serving as an internal negative control. Presence of pentamer (+) CD8 T cells indicated a p210-specific CD8+ T cell population. Patients positive for HLA-A 02:01 showed an average of 3.40 ± 2.17 × 10^3 HPF p210-specific CD8+ T cells (61.80%, 3% of total CD3+) in the shoulders of atherosclerotic plaques post-CEA, significantly higher than in controls (p < 0.0001). The proportion of p210-specific CD8+ T cells was lower in plaques displaying morphological features of instability. This study, for the first time, identifies a p210-specific CD8+ T cell population in human carotid atherosclerotic plaques from HLA-A02:01(+) patients, suggesting a role for autoimmunity in atherosclerosis development and supporting the potential efficacy of p210 immunization in HLA-A02:01 (+) individuals to reduce atherosclerosis. The variation in this specific T cell population within human plaques correlates with plaque vulnerability, highlighting p210-specific CD8+ T cells as a potential target for future therapies.
Paper
ZEB1 shapes AML immunological niches suppressing CD8 T-cell activity while fostering Th17 cell expansion
Acute myeloid leukemia (AML) development and progression is favored by immune suppression directly triggered by leukemia cells. ZEB1 is a key transcription factor in epithelial-to-mesenchymal transition which, we show here, is capable immune regulation in AML. Leukemic cells which had ZEB1 knocked down have reduced engraftment and extramedullary disease when transplanted into immune competent mice due to concomitant activation of CD8 T lymphocytes and reduced expansion of Th17 cells. Differently, in ZEB1 competent AML, IL-17 sustains the development of a pro-invasive and self-maintaining loop inducing MMPs and SOCS2. In humans, AML patients show, in situ on bone marrow biopsies, a direct correlation between ZEB1 and Th17 and, in gene expression profile when divided according to the median value of ZEB1 expression, a different overall survival and relapse along with the expression of MMPs, SOCS2 and Th17 cells enrichment. Overall, our data shed new light into the role of ZEB1 in AML that entwines both pro-tumoral and immune regulatory capacity in AML blasts.
Paper
SPARC regulation of PMN clearance protects from pristane induced lupus and rheumatoid arthritis
One step along the pathogenesis of Systemic lupus erythematosus (SLE) is associated with polymorphonuclear leukocyte (PMN) death and their ineffective removal by M2-macrophages. The secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein with unexpected immunosuppressive function in M2-macrophages and myeloid cells. To investigate the role of SPARC in autoimmunity, we adopted a pristane–induced model of lupus in mice, which recapitulates clinical manifestations of human SLE. Sparc-/- mice developed earlier and more severe renal disease, lung and liver parenchymal damage than the WT counterpart. Most prominently, Sparc-/- mice had anticipated and severe occurrence of arthritis. An intermediate phenotype was obtained in Sparc+/- hemizygous mice, a result that suggests Sparc gene-dosage as relevant in autoimmune-related events. Mechanistically, a defective Sparc expression in PMN blocks their clearance by macrophages, through a defective delivery of eat-me and don’t eat-me signals. Sparc-/- PMN that escape macrophage scavenging becomes a source of autoantigens for dendritic cell (DC) presentation and a direct stimulus for IL-17 expression in γδ-T-cells. Gene profile analysis of synovial biopsies of knees affected by SLE-associated arthritis showed an inverse correlation between SPARC and key autoimmune genes. These results point to SPARC down-regulation as a key event characterizing SLE and associated rheumatoid arthritis pathogenesis.
Paper