A systematic review of immunosuppressive protocols used in AAV gene therapy for monogenic disorders.

The emergence of adeno-associated virus (AAV)-based gene therapy has brought hope to patients with severe monogenic disorders. However, immune responses to AAV vectors and transgene products present challenges that require effective immunosuppressive strategies. This systematic review focuses on the immunosuppressive protocols used in 38 clinical trials and 35 real-world studies, considering a range of monogenic diseases, AAV serotypes, and administration routes.

Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis.

Glial cells and central nervous system (CNS)-infiltrating leukocytes contribute to multiple sclerosis (MS). However, the networks that govern crosstalk among these ontologically distinct populations remain unclear. Here, we show that, in mice and humans, CNS-resident astrocytes and infiltrating CD44CD4 T cells generated interleukin-3 (IL-3), while microglia and recruited myeloid cells expressed interleukin-3 receptor-ɑ (IL-3Rɑ).

Monocytes re-enter the bone marrow during fasting and alter the host response to infection.

Diet profoundly influences physiology. Whereas over-nutrition elevates risk for disease via its influence on immunity and metabolism, caloric restriction and fasting appear to be salutogenic. Despite multiple correlations observed between diet and health, the underlying biology remains unclear.

Sleep exerts lasting effects on hematopoietic stem cell function and diversity.

A sleepless night may feel awful in its aftermath, but sleep's revitalizing powers are substantial, perpetuating the idea that convalescent sleep is a consequence-free physiological reset. Although recent studies have shown that catch-up sleep insufficiently neutralizes the negative effects of sleep debt, the mechanisms that control prolonged effects of sleep disruption are not understood. Here, we show that sleep interruption restructures the epigenome of hematopoietic stem and progenitor cells (HSPCs) and increases their proliferation, thus reducing hematopoietic clonal diversity through accelerated genetic drift.

Brain motor and fear circuits regulate leukocytes during acute stress.

The nervous and immune systems are intricately linked. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood. Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice.

Quantity of IgG response to SARS-CoV-2 spike glycoprotein predicts pulmonary recovery from COVID-19.

The CovILD study is a prospective, multicenter, observational cohort study to systematically follow up patients after coronavirus disease-2019 (COVID-19). We extensively evaluated 145 COVID-19 patients at 3 follow-up visits scheduled for 60, 100, and 180 days after initial confirmed diagnosis based on typical symptoms and a positive reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We employed comprehensive pulmonary function and laboratory tests, including serum concentrations of IgG against the viral spike (S) glycoprotein, and compared the results to clinical data and chest computed tomography (CT).

Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease.

Communication within the glial cell ecosystem is essential for neuronal and brain health. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD.

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.

Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of T1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events.

Liver X receptors are required for thymic resilience and T cell output.

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)-a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity-critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire.

Growth Factors as Immunotherapeutic Targets in Cardiovascular Disease.

Growth factors, such as CSFs (colony-stimulating factors), EGFs (epidermal growth factors), and FGFs (fibroblast growth factors), are signaling proteins that control a wide range of cellular functions. Although growth factor networks are critical for intercellular communication and tissue homeostasis, their abnormal production or regulation occurs in various pathologies. Clinical strategies that target growth factors or their receptors are used to treat a variety of conditions but have yet to be adopted for cardiovascular disease.

Sleep modulates haematopoiesis and protects against atherosclerosis.

Sleep is integral to life. Although insufficient or disrupted sleep increases the risk of multiple pathological conditions, including cardiovascular disease, we know little about the cellular and molecular mechanisms by which sleep maintains cardiovascular health. Here we report that sleep regulates haematopoiesis and protects against atherosclerosis in mice.

Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.

The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways, how our bodies handle nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism. Here we describe a subset of immune cells-integrin β7 natural gut intraepithelial T lymphocytes (natural IELs)-that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism.

Self-reactive CD4 IL-3 T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis.

Acquisition of self-reactive effector CD4 T cells is a major component of the autoimmune response that can occur during myocarditis, an inflammatory form of cardiomyopathy. Although the processes by which self-reactive T cells gain effector function have received considerable attention, how these T cells contribute to effector organ inflammation and damage is less clear. Here, we identified an IL-3-dependent amplification loop that exacerbates autoimmune inflammation.

Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis.

Two distinct forms of the erythropoietin receptor (EPOR) mediate the cellular responses to erythropoietin (EPO) in different tissues. EPOR homodimers signal to promote the maturation of erythroid progenitor cells. In other cell types, including immune cells, EPOR and the ß-common receptor (CD131) form heteromers (the innate repair receptor; IRR), and exert tissue protective effects.

The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes.

Myocardial infarction (MI) elicits massive inflammatory leukocyte recruitment to the heart. Here, we hypothesized that excessive leukocyte invasion leads to heart failure and death during acute myocardial ischemia. We found that shortly and transiently after onset of ischemia, human and mouse cardiac fibroblasts produce granulocyte/macrophage colony-stimulating factor (GM-CSF) that acts locally and distally to generate and recruit inflammatory and proteolytic cells.

IL-27: a potential biomarker for responders to glatiramer acetate therapy.

Glatiramer acetate (GA) is an FDA-approved efficacious drug for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, this treatment is not effective for all RRMS patients. Therefore, it is important to identify reliable biomarkers that can predict a beneficial clinical response to GA therapy.

Advances in the immunopathogenesis of multiple sclerosis.

Purpose Of Review: Recent studies indicate a role for immune dysregulation in the pathogenesis of multiple sclerosis, an inflammatory demyelinating and degenerative disease of the central nervous system. This review addresses the current mechanisms of immune dysregulation in the development of multiple sclerosis, including the impact of environmental risk factors on immunity in both multiple sclerosis and its animal models.

Recent Findings: CD4 T-helper (Th) cells have long been implicated as the main drivers of pathogenesis of multiple sclerosis.

Early treatment with anti-VLA-4 mAb can prevent the infiltration and/or development of pathogenic CD11b+CD4+ T cells in the CNS during progressive EAE.

Natalizumab is a humanized monoclonal antibody against the leukocyte adhesion molecule very late antigen (VLA)-4, and is currently an approved therapy for patients with relapsing-remitting multiple sclerosis (RRMS). However, it is unknown whether natalizumab is beneficial for progressive forms of MS. Therefore, we assessed the effects of anti-VLA-4 monoclonal antibody (mAb) therapy in a progressive experimental autoimmune encephalomyelitis (EAE) mouse model.

Comparison of IFN-β inducible gene expression in primary-progressive and relapsing-remitting multiple sclerosis.

Interferon (IFN)-β is a type I IFN commonly produced by the innate immune system in response to viral infection. IFN-β is also used for the treatment of patients with the relapsing-remitting form of multiple sclerosis (RRMS); however, IFN-β therapy is unable to confer a significant benefit for primary-progressive MS (PPMS) patients. In this study, we assessed the gene profiles of peripheral blood mononuclear cells (PBMCs) isolated from PPMS, RRMS, and healthy donors (HD) in response to IFN-β treatment in vitro to examine genetic mechanisms underlying the inadequate response of IFN-β therapy in PPMS patients.