Metabolic Plasticity of Regulatory T Cells in Health and Autoimmunity.

Immunometabolism has been demonstrated to control immune tolerance and the pathogenic events leading to autoimmunity. Compelling experimental evidence also suggests that intracellular metabolic programs influence differentiation, phenotype, proliferation, and effector functions of anti-inflammatory CD4+CD25+Foxp3+ regulatory T (Treg) cells. Indeed, alterations in intracellular metabolism associate with quantitative and qualitative impairments of Treg cells in several pathological conditions. In this review, we summarize the most recent advances linking how metabolic pathways control Treg cell homeostasis and their alterations occurring in autoimmunity. Also, we analyze how metabolic manipulations could be employed to restore Treg cell frequency and function with the aim to create novel therapeutic opportunities to halt immune-mediated disorders.

Extracellular vesicles as human therapeutics: A scoping review of the literature.

Extracellular vesicles (EVs) are released by all cells and contribute to cell-to-cell communication. The capacity of EVs to target specific cells and to efficiently deliver a composite profile of functional molecules have led researchers around the world to hypothesize their potential as therapeutics. While studies of EV treatment in animal models are numerous, their actual clinical benefit in humans has more slowly started to be tested. In this scoping review, we searched PubMed and other databases up to 31 December 2023 and, starting from 13,567 records, we selected 40 pertinent published studies testing EVs as therapeutics in humans. The analysis of those 40 studies shows that they are all small pilot trials with a large heterogeneity in terms of administration route and target disease. Moreover, the absence of a placebo control in most of the studies, the predominant local application of EV formulations and the inconsistent administration dose metric still impede comparison across studies and firm conclusions about EV safety and efficacy. On the other hand, the recording of some promising outcomes strongly calls out for well-designed larger studies to test EVs as an alternative approach to treat human diseases with no or few therapeutic options.

Caloric restriction for the immunometabolic control of human health.

Nutrition affects all physiological processes occurring in our body, including those related to the function of the immune system; indeed, metabolism has been closely associated with the differentiation and activity of both innate and adaptive immune cells. While excessive energy intake and adiposity have been demonstrated to cause systemic inflammation, several clinical and experimental evidence show that calorie restriction (CR), not leading to malnutrition, is able to delay aging and exert potent anti-inflammatory effects in different pathological conditions. This review provides an overview of the ability of different CR-related nutritional strategies to control autoimmune, cardiovascular, and infectious diseases, as tested by preclinical studies and human clinical trials, with a specific focus on the immunological aspects of these interventions. In particular, we recapitulate the state of the art on the cellular and molecular mechanisms pertaining to immune cell metabolic rewiring, regulatory T cell expansion, and gut microbiota composition, which possibly underline the beneficial effects of CR. Although studies are still needed to fully evaluate the feasibility and efficacy of the nutritional intervention in clinical practice, the experimental observations discussed here suggest a relevant role of CR in lowering the inflammatory state in a plethora of different pathologies, thus representing a promising therapeutic strategy for the control of human health.

Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential.

Human CD4+CD25hiFOXP3+ regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.

Legislative proposal in Italy to facilitate contacts between deceased organ donor families and transplant recipients.

Contacts between organ donors and recipients might be possible in the near future in Italy. As suggested by The Italian Committee of Bioethics "anonymity is requested by the Italian National Transplant Centre" before transplantation anonymity shall be strict in order to grant privacy, gratuity, justice, solidarity and benefits and avoids organ trafficking. Following a period that is ethically correct and justifiable, organ donor families and recipients can meet after signing a valid declaration of consent, expressed on a template valid for the whole country. A third party within the body of the National Health Systems shall control the validity of the consent. The opinion stresses that contacts are not a right but a possibility justifiable on ethical grounds if the procedure is followed appropriately. A legislative proposal has been presented before the Chamber of deputies incorporating all suggestions made by the National Committee of Bioethics. The agreement between parties might be signed a year after transplantation. This is a long enough period of time for the recipients to fully appreciate the benefits of the procedure and for the donor families to see the effects of their decision (the opinion and the Law proposal hit the Zeitgeist, and keep Italy in the regulation of European Union).

[Laws regulating transplantation should express the contemporaneity. Questions to the constitutionalist Francesco Paolo Casavola and to the philosophers Remo Bodei and Aldo Masullo about the possibility deciding the destiny of one's own organs at the time one decides on how to die and on contacts between donor families and recipients.]

Transplantation represents modernity thus the laws regulating the procedure should be continuously renovated and remodeled in order to take full advantage of progress. The debate is about Law no. 219, December 22, 2017 and on Law no. 222, April 1, 1999. The quests are a) about the possibility to modify the first so that people deciding on how they want to die, may also decide about their willingness to allow the removal of their organs for transplantation and b) the possibility for donor families and recipients to have contacts after transplantation in the case both sides agree. Questions were emailed to the constitutionalist Francesco Paolo Casavola, immediate Past President of the National Committee for Bioethics, and to the philosophers Remo Bodei and Aldo Masullo. Their answers received by September 16, support the idea a) to include in the Law no. 219, 2017 the possibility to decide not only on the modality one wants to die but also on the possibility to allow his own organs to be removed for transplantation and b) to liberalize contacts between donor families and recipients when both side agree. For both changes there is enough evidence of their feasibility-necessity. The answers related to contacts between donor families and recipients support the decision of the National Committee for Bioethics on September 27, 2018. Professor Casavola also suggests that contacts should organized and supervised by the ethical committees of the hospitals where the transplantation procedure is accomplished.

[The Italian Places of Nicholas Green 20 years after his assassination]. / I luoghi italiani di Nicholas Green venti anni dopo il suo assassinio

Twenty years ago, Nicholas Green, a 7- year-old American boy was shot, while on vacation, on the Autostrada (motorway) Salerno to Reggio Calabria in Italy. His organs, with the consent of his parents, Reg and Maggie, were removed and 7 persons had their lives changed. In Italy in these last 20 years, organ donation has increased powerfully from 6.2 to 18.2 per million population with a peak at 20 in 2006. Reg and Maggie Green, after Nicholas death, started campaigning for organ donation by making full use of the media. Italian justice was efficient and the criminals were imprisoned quickly. With popular enthusiasm, a total of 103 places were dedicated to Nicholas (schools, halls, squares, streets, parks, gardens, private collections), a proof of great appreciation. Teaching organ donation to children, nurses and medical students is a powerful tool to convey the message of organ donation. To prevent opposition to organ removal when brain death occurs as Professor Francesco Casavola says signing for organ donation should be a family decision and laws for organ donation should be updated frequently in order to meet the progress of modernity.