The spleen assumes a major role in blood glucose regulation in type 1 diabetes patients treated with BCG.

The Bacillus Calmette-Guérin (BCG) vaccine, which has been used for > 100 years to prevent tuberculosis, is well-established for bladder cancer treatment, and under study for neurological and autoimmune diseases. In patients with type 1 diabetes (T1D), BCG vaccinations have been shown in randomized clinical trials to gradually lower blood sugar to near normal levels. This effect appears to be driven by a BCG-induced shift in lymphoid cells' glucose metabolism from oxidative phosphorylation to aerobic glycolysis.

Late in the US pandemic, multi-dose BCG vaccines protect against COVID-19 and infectious diseases.

The Bacillus Calmette-Guérin vaccine has many off-target benefits, including protection from diverse infectious diseases. As SARS-CoV-2 evolved, COVID-19 disease became more transmissible and less lethal. In this Phase III double-blinded, placebo-controlled trial conducted late in the pandemic, we tested at-risk US adults with type 1 diabetes if multi-dose BCG protected against COVID-19 and other infectious disease, co-primary outcomes.

Transmembrane TNF-TNFR2 signaling as a critical immunoregulatory node in pancreatic cancer.

Pancreatic cancer is characterized by extreme therapeutic resistance. In pancreatic cancers harboring high-risk genomes, we describe that cancer cell-neutrophil signaling circuitry provokes neutrophil-derived transmembrane (tm)TNF-TNFR2 interactions that dictate inflammatory polarization in cancer-associated fibroblasts and T-cell dysfunction - two hallmarks of therapeutic resistance. Targeting tmTNF-TNFR2 signaling may sensitize pancreatic cancer to chemo±immunotherapy.

The benefits of clustering in TNF receptor superfamily signaling.

The tumor necrosis factor (TNF) receptor superfamily is a structurally and functionally related group of cell surface receptors that play crucial roles in various cellular processes, including apoptosis, cell survival, and immune regulation. This review paper synthesizes key findings from recent studies, highlighting the importance of clustering in TNF receptor superfamily signaling. We discuss the underlying molecular mechanisms of signaling, the functional consequences of receptor clustering, and potential therapeutic implications of targeting surface structures of receptor complexes.

Association of BCG Vaccine Treatment With Death and Dementia in Patients With Non-Muscle-Invasive Bladder Cancer.

Importance: The BCG vaccine-used worldwide to prevent tuberculosis-confers multiple nonspecific beneficial effects, and intravesical BCG vaccine is currently the recommended treatment for non-muscle-invasive bladder cancer (NMIBC). Moreover, BCG vaccine has been hypothesized to reduce the risk of Alzheimer disease and related dementias (ADRD), but previous studies have been limited by sample size, study design, or analyses.

Objective: To evaluate whether intravesical BCG vaccine exposure is associated with a decreased incidence of ADRD in a cohort of patients with NMIBC while accounting for death as a competing event.

Bacille Calmette Guerin (BCG) and prevention of types 1 and 2 diabetes: Results of two observational studies.

Background: Diabetes is a common disease marked by high blood sugars. An earlier clinical trial in type 1 diabetic subjects (T1Ds) found that repeat BCG vaccinations succeeded in lowering HbA1c values over a multi-year course. Here we seek to determine whether BCG therapy for bladder cancer may improve blood sugar levels in patients with comorbid T1D and type 2 diabetes (T2D).

BCG vaccinations drive epigenetic changes to the human T cell receptor: Restored expression in type 1 diabetes.

The BCG (Bacille Calmette-Guérin) vaccine, introduced 100 years ago for tuberculosis prevention, has emerging therapeutic off-target benefits for autoimmunity. In randomized controlled trials, BCG vaccinations were shown to gradually improve two autoimmune conditions, type 1 diabetes (T1D) and multiple sclerosis. Here, we investigate the mechanisms behind the autoimmune benefits and test the hypothesis that this microbe synergy could be due to an impact on the host T cell receptor (TCR) and TCR signal strength.

TNFR2 antagonistic antibody induces the death of tumor infiltrating CD4Foxp3 regulatory T cells.

Background: TNFR2 expression is a characteristic of highly potent immunosuppressive tumor infiltrating CD4Foxp3 regulatory T cells (Tregs). There is compelling evidence that TNF through TNFR2 preferentially stimulates the activation and expansion of Tregs. We and others, therefore, proposed that targeting TNFR2 may provide a novel strategy in cancer immunotherapy.

Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes.

There is a need for safe and effective platform vaccines to protect against coronavirus disease 2019 (COVID-19) and other infectious diseases. In this randomized, double-blinded, placebo-controlled phase 2/3 trial, we evaluate the safety and efficacy of a multi-dose Bacillus Calmette-Guérin (BCG) vaccine for the prevention of COVID-19 and other infectious disease in a COVID-19-unvaccinated, at-risk-community-based cohort. The at-risk population is made of up of adults with type 1 diabetes.

The Roles of TNFR2 Signaling in Cancer Cells and the Tumor Microenvironment and the Potency of TNFR2 Targeted Therapy.

The appreciation that cancer growth is promoted by a dynamic tumor microenvironment (TME) has spawned novel approaches to cancer treatment. New therapies include agents that activate quiescent T effector cells and agents that interfere with abnormal neovascularity. Although promising, many experimental therapies targeted at the TME have systemic toxicity.

Signal Amplification in Highly Ordered Networks Is Driven by Geometry.

Here, we hypothesize that, in biological systems such as cell surface receptors that relay external signals, clustering leads to substantial improvements in signaling efficiency. Representing cooperative signaling networks as planar graphs and applying Euler's polyhedron formula, we can show that clustering may result in an up to a 200% boost in signaling amplitude dictated solely by the size and geometry of the network. This is a fundamental relationship that applies to all clustered systems regardless of its components.

A TNFR2 antibody by countering immunosuppression cooperates with HMGN1 and R848 immune stimulants to inhibit murine colon cancer.

Immunosuppressive CD4Foxp3 regulatory T cells (Tregs) promote tumor immune evasion and thus targeting of Tregs has become an strategy in cancer immunotherapy. Tumor necrosis factor receptor 2 (TNFR2) is highly expressed and important for the immunosuppressive function of Tregs in humans and mice. Thus, the benefit of targeting TNFR2 in cancer immunotherapy merits more investigation.

Bacillus Calmette-Guerin 's beneficial impact on glucose metabolism: evidence for broad based applications.

Bacillus Calmette-Guerin (BCG) vaccinations improve glycemic control in juvenile-onset Type I diabetes (T1D), an effect driven by restored sugar transport through aerobic glycolysis. In a pilot clinical trial, T1D, but not latent autoimmune diabetes of adults (LADA), exhibited lower blood sugars after multidose BCG. Using a glucose transport assay, monocytes from T1D subjects showed a large stimulation index with BCG exposures; LADA subjects showed minimal BCG-induced sugar responsiveness.

BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation.

Induction of immunosuppressive T-regulatory cells (Tregs) is a desirable goal in autoimmunity, and perhaps other immune diseases of activation. One promising avenue is with the bacille-calmette-guérin (BCG) vaccine in autoimmune type 1 diabetes (T1D). Its administration is associated with gradual clinical improvements in human autoimmunity over a 2-3 year post-vaccination period.

Epigenetic changes related to glucose metabolism in type 1 diabetes after BCG vaccinations: A vital role for KDM2B.

Background: A recent epigenome-wide association study of genes associated with type 2 diabetics (T2D), used integrative cross-omics analysis to identify 22 abnormally methylated CpG sites associated with insulin and glucose metabolism. Here, in this epigenetic analysis we preliminarily determine whether the same CpG sites identified in T2D also apply to type 1 diabetes (T1D). We then determine whether BCG vaccination could correct the abnormal methylation patterns, considering that the two diseases share metabolic derangements.

A novel TNFR2 agonist antibody expands highly potent regulatory T cells.

Regulatory T cells (T cells) restrict immune system activity, such as in response to self-antigens, and are switched on by tumor necrosis factor receptor 2 (TNFR2). Therapeutic activation of TNFR2, thereby expanding T cells and suppressing immune activity, may be beneficial to patients with various inflammatory diseases. Here, we characterized a new human TNFR2-directed antibody agonist isolated from mice.

TIPICO X: report of the 10th interactive infectious disease workshop on infectious diseases and vaccines.

TIPICO is an expert meeting and workshop that aims to provide the most recent evidence in the field of infectious diseases and vaccination. The 10th Interactive Infectious Disease TIPICO workshop took place in Santiago de Compostela, Spain, on November 21-22, 2019. Cutting-edge advances in vaccination against respiratory syncytial virus, , rotavirus, human papillomavirus, , influenza virus, and Typhi were discussed.

Brucella abortus and Pregnancy in Mice: Impact of Chronic Infection on Fertility and the Role of Regulatory T Cells in Tissue Colonization.

Stealthy intracellular bacterial pathogens are known to establish persistent and sometimes lifelong infections. Some of these pathogens also have a tropism for the reproductive system, thereby increasing the risk of reproductive disease and infertility. To date, the pathogenic mechanism involved remains poorly understood.

TNFR2 blockade alone or in combination with PD-1 blockade shows therapeutic efficacy in murine cancer models.

Immune checkpoint inhibitors are profoundly transforming cancer therapy, but response rates vary widely. The efficacy of checkpoint inhibitors, such as anti-programmed death receptor-1 (anti-PD-1), might be increased by combination therapies. TNFR2 has emerged as a new target due to its massive expression on highly immunosuppressive regulatory T cells (Tregs) in the microenvironment and on certain tumor cells.

BCG Vaccinations Upregulate Myc, a Central Switch for Improved Glucose Metabolism in Diabetes.

Myc has emerged as a pivotal transcription factor for four metabolic pathways: aerobic glycolysis, glutaminolysis, polyamine synthesis, and HIF-1α/mTOR. Each of these pathways accelerates the utilization of sugar. The BCG vaccine, a derivative of Mycobacteria-bovis, has been shown to trigger a long-term correction of blood sugar levels to near normal in type 1 diabetics (T1D).

On the TRAIL of Better Therapies: Understanding TNFRSF Structure-Function.

Tumor necrosis factor (TNF) superfamily ligands show diverse biological functions, such as the induction of apoptotic cell death or cell survival and proliferation, making them excellent therapeutic targets for cancer and autoimmunity. We review the latest literature on TNF receptor superfamily signaling with a focus on structure-function. Using combinatorics, we argue that receptors that cluster on the cell surface and are activated by membrane-bound ligands need to arrange in a highly ordered manner, as the probability of random ligand and receptor arrangements matching up for receptor activation is very low.

Optimizing TNFR2 antagonism for immunotherapy with tumor microenvironment specificity.

Most approved cancer immunotherapies lack T-regulatory (Treg) or tumor specificity. TNF receptor 2 (TNFR2) antibody antagonism is emerging as an attractive immunotherapy due to its tumor microenvironment (TME) specificity. Here we show that the human TNFR2 receptor is overexpressed on both human tumor cells and on human tumor-residing Tregs, but negligibly expressed on beneficial T effectors (Teffs).

Benefits of BCG-induced metabolic switch from oxidative phosphorylation to aerobic glycolysis in autoimmune and nervous system diseases.

The most commonly used vaccine worldwide, bacillus Calmette-Guerin (BCG), appears to have the ability to restore blood sugar control in humans with early-onset but long-duration type 1 diabetes when a repeat vaccination strategy is used. This is a process that may be driven by a metabolic switch from overactive oxidative phosphorylation to accelerated aerobic glycolysis and a reset of the immune system. BCG is a live, attenuated strain of Mycobacteria bovis, a cousin of M.