Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic β cells. We herein investigated the role of GLP-1R on T lymphocytes during immune response. Our data showed that a subset of T lymphocytes expresses GLP-1R, which is upregulated during alloimmune response, similarly to PD-1. When mice received islet or cardiac allotransplantation, an expansion of GLP-1Rpos T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA sequencing (scRNA-seq) analysis conducted on GLP-1Rpos and GLP-1Rneg CD3+ T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1Rpos are mainly composed of exhausted CD8 T cells. GLP-1R acts as a T cell-negative costimulatory molecule, and GLP-1R signaling prolongs allograft survival, mitigates alloimmune response, and reduces T lymphocyte graft infiltration. Notably, GLP-1R antagonism triggered anti-tumor immunity when tested in a preclinical mouse model of colorectal cancer.

Purpose of review: The purine nucleotide adenosine triphosphate (ATP) is released into extracellular spaces as extracellular ATP (eATP) as a consequence of cell injury or death and activates the purinergic receptors. Once released, eATP may facilitate T-lymphocyte activation and differentiation. The purpose of this review is to elucidate the role of ATP-mediated signaling in the immunological events related to type 1 diabetes (T1D). Recent findings: T lymphocytes mediate immune response during the onset of T1D and promote pancreatic islet or whole pancreas rejection in transplantation. Recent data suggest a potential role for eATP in early steps of T1D onset and of allograft rejection. In different preclinical experimental models and clinical trials, several drugs targeting purinergic signaling have been employed to abrogate lymphocyte activation and differentiation, thus representing an achievable treatment to prevent/revert T1D or to induce long-term islet allograft function. Summary: In preclinical and clinical settings, eATP-signaling inhibition induces immune tolerance in autoim-mune disease and in allotransplantation. In this view, the purinergic system may represent a novel therapeutic target for auto-and allo-immunity.

Glucagon Like Peptide-1 Receptor (GLP1R) is a key regulator of glucose metabolism, known to be expressed by pancreatic β-cells, gastric mucosa and hypothalamus. Recently, GLP1R mRNA has been detected on T lymphocytes; however, its function in these cells remains poorly understood. We herein investigated the role of GLP1R on T lymphocytes during immune response. Our data showed that a subset of naïve CD4 and CD8 T lymphocytes expresses GLP1R in humans and mice, while GLP1R appeared to have a unique interactome pattern in T lymphocytes different from those of pancreatic β-cells. Interestingly, the presence of GLP1R delineates a population of activated T cells which are more prone to cell death. GLP1R is upregulated in vitro and in vivo during alloimmune response, similarly to PD-1 and CTLA4. When C57BL/6 mice received islet or cardiac allotransplantation from a fully mismatched BALB/c donor, an expansion of GLP1R+ CD4+/CD8+ T cells occurred in the spleen and were found to infiltrate the graft. Importantly, when signaling through GLP1R with an agonist, T cell pathways of apoptosis and senescence are upregulated with significant prolongation of cardiac and islet allograft survival and reduced graft T lymphocytes infiltrate. The gene-repression protein Baz2a appeared to be responsible for driving the GLP1R-dependent T cell negative costimulation. Genetic GLP1R gain of function is associated with T cell activation and cell death, while GLP1RKO accelerate chronic allograft rejection. GLP1R acts as a T cell negative costimulatory molecule and GLP1R signaling prolongs allograft survival, mitigates alloimmune response and reduces T lymphocytes graft infiltration.

Purpose: A clinical trial was conducted to evaluate the activity of a new artificial tear containing hyaluronic acid (HA) and low-dose hydrocortisone to control dry-eye disease (DED) symptoms.Methods: a randomized, controlled, double-masked study was carried out at the Ocular Surface and Dry Eye Center, "Luigi Sacco" University Hospital (Milan, Italy), between June 2020 and June 2021. The study involved patients with DED for at least 6 months. After an initial 7-day treatment with corticosteroid, the treatment with the new artificial tear (four-times a day for 6 months) was compared with a control HA solution.Results: A total of 40 patients were considered. We observed a significant improvement in the frequency and intensity of DED symptoms in both groups. After corticosteroid discontinuation, the maintenance of the therapeutic advantage was observed only in the treatment group, which also showed a significant improvement of the tear film break-up time (p & LE; 0.05) and infiltrated macrophages (p < 0.05). A significant reduction in fluorescein and Lissamine staining (p < 0.05) was observed in the treatment group, suggesting damage reduction at both corneal and conjunctival levels. Intraocular pressure did not change at the end of the treatment period and was maintained within the normal range, sustaining the product's safety.Conclusions: Our findings support the prolonged use of the new eye drop with low-dose hydrocortisone, also in the DED initial stages, to prevent the degenerating towards a chronic condition ().

The aim of this retrospective study was to evaluate risk factors for 3-years mortality after hospital discharge in all inpatients admitted to a general hospital in Milano, Italy. A total of 2580 consecutive patients admitted to Ospedale San Paolo, July 1 to December 31, 2012, for several classes of diseases (internal medicine, cancer, infectious diseases, trauma and surgery, pneumonia, and heart diseases) were studied. Age, total disease, type of admission, length of admission, age-adjusted Charlson index, prognostic nutritional index (PNI), and full blood count were evaluated. Univariate Cox models were used to evaluate the association between variables and death. Of the 2580 consecutive patients (age 66.8 ± 19.36 years, mean ± SD), 920 died within 3 years after discharge. At univariate analysis, all investigated variables, except sex and lymphocytes, were associated with patient death. Stepwise regression analyses revealed that the age-adjusted Charlson index or age plus total diseases, type of admission, number of admissions, and PNI were significant risk factors in the whole sample and in some classes of disease. Results were superimposable when considering death from date of admission instead of date of discharge, meaning that in-hospital death was not relevant to the total death count (115 out of 902). Seriousness of baseline conditions represents the major risk factor for mortality in most classes of disease, and possibly influences other predictors, such as type of admission and length of stay. This suggests that the current model of hospital admission might be improved, for instance, through comprehensive care at home, instead of hospital admission, or before admission.

Background: Survival after hospital admission has been evaluated as a possible risk factor for long-term mortality in selected classes of diseases. The aim of this study was to evaluate survival after hospital admission in all patients admitted as in-patients in a general hospital of Milano, Italy.Methods: 2,580 consecutive patients admitted at Ospedale San Paolo, July1-December 31, 2012, for several classes of diseases (internal medicine, cancer, infectious diseases, trauma and surgery, pneumonia, and heart diseases) were studied; age, total diseases, type of admission, length of admission, age-adjusted Charlson index, prognostic nutritional index (PNI), and full blood count were evaluated.Results: At univariate analysis, all investigated variables, except sex and lymphocytes, were associated with death of patients. At stepwise regression analysis, Charlson index or age plus total diseases, type of admission, number of admissions, and PNI were significant risk factors in the whole sample and in the majority of classes of diseases.Conclusion: Pre-existing conditions and nutritional state represent the major risk factor for mortality in most classes of disease, and possibly influence other predictors, such as type of admission, length of stay. This suggests that the current model of hospital admission might be improved, for instance through comprehensive care at home, instead of hospital admission, or before admission.Funding Information: This study received only institutional funds from Università degli Studi di Milano and from IRCCS Multimedica; a grant by the Italian Ministry of Health (Ministero della Salute), was issued to IRCCS Multimedica (Ricerca Corrente).Declaration of Interests: LL, FG, ASZ, MF, AV, AEP, and ET declare no conflict of interest with the content of this paper.Ethics Approval Statement: The protocol of the study was approved by the local Ethics in 2013 (original study) and in 2020 (follow-up study).

Weight loss in patients with metabolic syndrome has positive effects on cardiovascular and type 2 diabetes risks, but its effects on peripheral cytokines and lipid profiles in patients are still unclear. To determine the effects of diet-induced weight loss on metabolic parameters, lipids and cytokine profiles. Eighteen adult males with metabolic syndrome (defined according to IDF 2009) and Body Mass Index (BMI) between 25 and 35 kg/m2 were subjected to a balanced hypocaloric diet for 6 months to reach at least a 5% body weight loss. After weight loss, a significant improvement in BMI, waist circumference, insulin, fasting blood glucose and HOMA-IR (homeostasis model assessment of insulin resistance) was observed. The analysis of LDL (low-density lipoprotein cholesterol) and HDL (high-density lipoprotein cholesterol) lipoproteins showed a change in their composition with a massive transfer of triacylglycerols from HDL to LDL. This was associated with a significant reduction in peripheral pro-inflammatory cytokines such as IL-6, TNF-α, IL-8 and MIP-1β, leading to an overall decreased inflammatory score. An interesting positive correlation was also observed among peripheral cytokines levels after diet and peripheral levels of CETP (cholesteryl ester transfer protein), an enzyme with a key role in lipid change. Weight loss through caloric restriction is associated with an improvement in peripheral lipid and cytokine profiles that may play a major role in improving cardiovascular risk.

tutor: G.V. Zuccotti ; coordinatore: L. Pinotti ; supervisore: P. Fiorina ; revisore: D. Corradi; revisore: A. Secchi

Background: Nowadays obesity is the world’s common disease. Bariatric surgery is the only therapy that provides significant cost savings within Public Health Service, but the lack of diagnostic paths universally accepted causes enormous waste of resources and disruptions. Service Mapping is the ideal methodology to describe work’s organization and to plan a new service model. Methods: The Service Mapping has been used to represent the actual state of the bariatric surgery service and starting from the critical aspects found, we have developed a desirable state of the service. Results: Experience-based design has given centrality to the beneficiary, making the bariatric service sensitive to patient’s needs and expectations. The micro-organization of work has improved professionals’ integration, avoiding the creation of new operational entities or additional costs. The service has been simplified both for clinicians and hospital managers. The strategic repositioning of the dietician and general practitioner’s recognition within the bariatric path allowed us to achieve better clinical outcomes. Conclusions: Service Mapping has highlighted clinicians’ difficulties in providing the service, emphasizing the importance of the beneficiary. The iconic representation is a powerful explicit framework, fundamental for management purposes, to understand the role of every subject involved in the service, to rationalize work’s organization, and integrate healthcare activities.

An amendment to this paper has been published and can be accessed via the original article.