Wnt-Activated Immunoregulatory Myeloid Cells Prevent Relapse in Experimental Autoimmune Encephalomyelitis and Offer a Potential Therapeutic Strategy for Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by recurrent inflammatory relapses and neurodegeneration. Myeloid cells play a critical role in shaping the inflammatory environment and influencing disease progression. Here, we demonstrate that activation of the Wnt signaling pathway reprograms myeloid cells into an immunoregulatory phenotype, leading to reduced neuroinflammation and disease severity.

AA147 Alleviates Symptoms in a Mouse Model of Multiple Sclerosis by Reducing Oligodendrocyte Loss.

Inflammation-induced oligodendrocyte death and CNS demyelination are key features of multiple sclerosis (MS). Inflammation-triggered endoplasmic reticulum (ER) stress and oxidative stress promote tissue damage in MS and in its preclinical animal model, experimental autoimmune encephalitis (EAE). Compound AA147 is a potent activator of the ATF6 signaling arm of the unfolded protein response (UPR) that can also induce antioxidant signaling through activation of the NRF2 pathway in neuronal cells.

Activation of limbal epithelial proliferation is partly controlled by the ACE2-LCN2 pathway.

In response to corneal injury, an activation of corneal epithelial stem cells and their direct progeny the early transit amplifying (eTA) cells to rapidly proliferate is critical for proper re-epithelialization. Thus, it is important to understand how such stem/eTA cell activation is regulated. Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed in the stem/eTA-enriched limbal epithelium but its role in the limbal epithelium was unclear.

Therapeutic role of interferon-γ in experimental autoimmune encephalomyelitis is mediated through a tolerogenic subset of splenic CD11b myeloid cells.

Cumulative evidence has established that Interferon (IFN)-γ has both pathogenic and protective roles in Multiple Sclerosis and the animal model, Experimental Autoimmune Encephalomyelitis (EAE). However, the underlying mechanisms to the beneficial effects of IFN-γ are not well understood. In this study, we found that IFN-γ exerts therapeutic effects on chronic, relapsing-remitting, and chronic progressive EAE models.

Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes.

Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (I) were recently identified in mature OLG and shown to play a role in regulating myelin length.

Rotator Cuff Tears Are Related to the Side Sleeping Position.

Purpose: To determine whether there was a relationship between sleep position and symptomatic partial- and full-thickness rotator cuff tears.

Methods: A consecutive series of patients that met the inclusion/exclusion criteria (n = 58) were in seen in clinic between July 2019 and December 2019. All of these individuals had a significant partial-thickness (> 50%) or full-thickness rotator cuff tear determined by either ultrasound, magnetic resonance imaging, or both.

The immune system and metabolic products in epilepsy and glioma-associated epilepsy: emerging therapeutic directions.

Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have drug-refractory epilepsy and are nonresponsive to medical treatment. Nearly all currently approved ASMs target neuronal activity through ion channel modulation.

Interferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (Th17) and antibody responses to the water channel protein, aquaporin 4 (AQP4), and associated with astrocytopathy, demyelination and axonal loss. Knowledge about disease pathogenesis is limited and the search for new therapies impeded by the absence of a reliable animal model. In our work, we determined that NMOSD is characterized by decreased IFN-γ receptor signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD.

Engineering nanoparticle therapeutics for food allergy.

Food allergy is a growing public health issue among children and adults that can lead to life-threatening anaphylaxis following allergen exposure. The criterion standard for disease management includes food avoidance and emergency epinephrine administration because current allergen-specific immunotherapy treatments are limited by adverse events and unsustained desensitization. A promising approach to remedy these shortcomings is the use of nanoparticle-based therapies that disrupt disease-driving immune mechanisms and induce more sustained tolerogenic immune pathways.

Topical application of synthetic melanin promotes tissue repair.

In acute skin injury, healing is impaired by the excessive release of reactive oxygen species (ROS). Melanin, an efficient scavenger of radical species in the skin, performs a key role in ROS scavenging in response to UV radiation and is upregulated in response to toxic insult. In a chemical injury model in mice, we demonstrate that the topical application of synthetic melanin particles (SMPs) significantly decreases edema, reduces eschar detachment time, and increases the rate of wound area reduction compared to vehicle controls.

Nanoparticle dose and antigen loading attenuate antigen-specific T-cell responses.

Immune-mediated hypersensitivities such as autoimmunity, allergy, and allogeneic graft rejection are treated with therapeutics that suppress the immune system, and the lack of specificity is associated with significant side effects. The delivery of disease-relevant antigens (Ags) by carrier systems such as poly(lactide-co-glycolide) nanoparticles (PLG-Ag) and carbodiimide (ECDI)-fixed splenocytes (SP-Ag) has demonstrated Ag-specific tolerance induction in model systems of these diseases. Despite therapeutic outcomes by both platforms, tolerance is conferred with different efficacy.

Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma.

The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because of innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa and hypothesized that EZH2 inhibition, via a small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, in a carcinogen-induced mouse bladder cancer model, a reduction in tumor progression and an increase in immune infiltration upon EZH2 inhibition were observed.

Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity.

Tolerogenic Immune-Modifying Nanoparticles Encapsulating Multiple Recombinant Pancreatic β Cell Proteins Prevent Onset and Progression of Type 1 Diabetes in Nonobese Diabetic Mice.

Type 1 diabetes (T1D) is an autoimmune disease characterized by T and B cell responses to proteins expressed by insulin-producing pancreatic β cells, inflammatory lesions within islets (insulitis), and β cell loss. We previously showed that Ag-specific tolerance targeting single β cell protein epitopes is effective in preventing T1D induced by transfer of monospecific diabetogenic CD4 and CD8 transgenic T cells to NOD. mice.

Masked Delivery of Allergen in Nanoparticles Safely Attenuates Anaphylactic Response in Murine Models of Peanut Allergy.

Food allergy is a growing health concern worldwide. Current allergen-specific immunotherapy (AIT) approaches require frequent dosing over extended periods of time and may induce anaphylaxis due to allergen-effector cell interactions. A critical need remains to develop novel approaches that refine AIT for the treatment of food allergies.

Mechanistic contributions of Kupffer cells and liver sinusoidal endothelial cells in nanoparticle-induced antigen-specific immune tolerance.

The intravenous delivery of disease-relevant antigens (Ag) by polymeric nanoparticles (NP-Ags) has demonstrated Ag-specific immune tolerance in autoimmune and allergic disorders as well as allogeneic transplant rejection. NP-Ags are observed to distribute to the spleen, which has an established role in the induction of immune tolerance. However, studies have shown that the spleen is dispensable for NP-Ag-induced tolerance, suggesting significant contributions from other immunological sites.

PLG nanoparticles target fibroblasts and MARCO+ monocytes to reverse multiorgan fibrosis.

Systemic sclerosis (SSc) is a chronic, multisystem orphan disease with a highly variable clinical course, high mortality rate, and a poorly understood complex pathogenesis. We have identified an important role for a subpopulation of monocytes and macrophages characterized by surface expression of the scavenger receptor macrophage receptor with collagenous structure (MARCO) in chronic inflammation and fibrosis in SSc and in preclinical disease models. We show that MARCO+ monocytes and macrophages accumulate in lesional skin and lung in topographic proximity to activated myofibroblasts in patients with SSc and in the bleomycin-induced mouse model of SSc.

Tolerogenic Delivery of a Hybrid Insulin Peptide Markedly Prolongs Islet Graft Survival in the NOD Mouse.

The induction of antigen (Ag)-specific tolerance and replacement of islet β-cells are major ongoing goals for the treatment of type 1 diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4+ T cells in the NOD mouse model.

Can Immune Tolerance Be Re-established in Neuromyelitis Optica?

Neuromyelitis optica (NMO) is a chronic inflammatory disease of the central nervous system that primarily affects the optic nerves and spinal cord of patients, and in some instances their brainstem, diencephalon or cerebrum as spectrum disorders (NMOSD). Clinical and basic science knowledge of NMO has dramatically increased over the last two decades and it has changed the perception of the disease as being inevitably disabling or fatal. Nonetheless, there is still no cure for NMO and all the disease-modifying therapies (DMTs) are only partially effective.