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New Immunomodulatory Compounds

Regulatory T cells (Treg) play a critical role in controlling immune responses, chronic inflammation and autoimmune disease. Integrin activation in CD4+ FoxP3+ Treg is crucial to the maintenance of Treg numbers and function in vivo. Tregs also express high levels of the low affinity IL2 receptor CD25 (IL2Ra, TAC) on their cell surface. One mechanism by which Tregs are thought to limit immune responses is by sequestering the available IL2, effectively starving effectors and leading to peripheral tolerance. Previous work by the inventors showed that activation of integrin adhesion receptors were critical to the functioning and maintenance of peripheral Tregs. The present invention describes antibodies that specifically activate integrins on Tregs but not on conventional T cells. These antibodies promote the proliferation and outgrowth of Tregs but not of conventional T cells in vitro.   Thus, treatment with such antibodies would be expected to ameliorate auto-immunity.

Use of Thiazolidinediones for Treatment of Eosinophilic Esophagitis Pathologic Remodeling

Esophageal inflammatory disorders are gaining increased recognition in both adults and children. One example is eosinophilic esophagitis (EoE), which is an emerging and fast-growing disorder characterized by high levels of eosinophils in the esophagus, as well as esophageal cellular changes such as basal zone hyperplasia and esophageal remodeling that includes fibrosis and smooth muscle dysfunction. These complications can lead to trouble swallowing, strictures,and food impactions. EoE is thought to be provoked, in at least a subset of patients, by food allergies or airborne allergen exposure. EoE diagnosis is often associated with other hypersensitivity disorders, including asthma, rhinitis, and other food and aeroallergen inhalant sensitivities. Diagnosis requires the finding of 15 or more eosinophils per high power field (eos/hpf) within esophageal mucosal biopsies. Although EoE is becoming more frequently diagnosed throughout developing countries, many aspects of the disease remain unclear including its etiology, natural history and optimal therapy. Symptoms of EoE often mimic those of gastroesophageal reflux disease (GERD) and include vomiting, dysphagia, pain and food impaction. In the absence of long-term treatment, up to 70-80% of adults with eosinophilic esophagitis (EoE) may go on to develop esophageal strictures. This disease now is likely to occur in 1 in 1000 people in the population and will have a dramatic effect on the patients’ quality of life. While there are therapies that control inflammation, not all patients respond to these therapies and continue to progress to fibrotic changes. There are currently no medical treatments to directly target esophageal fibrosis.

Use of Gene Therapy to Treat Joint Disease and Synovial Tumors

The National Center for Advancing Translational Sciences and Genetic and Rare Diseases Information Center characterizes Pigmented villonodular synovitis (PVNS) as a rare disease estimated to occur in ~ 5-6 people out of 100,000. This locally invasive tumor most often occurs in younger adults and causes severe damage to joints. The first line of treatment is surgery but at least 50% of patients require multiple surgeries over many years due to re-growth of the tumor.

TRM:CRAMP Knockout Mice In The C57bl/6 Background

The mouse Camp gene is an ortholog of the human gene CAMP, which encodes the precursor of cathelicidin antimicrobial peptide LL-37 (or CRAMP in mouse). Expressed mucosal epithelial cells, circulating neutrophils, and myeloid bone marrow cells, Camp is an essential part of the first line of defense against infection. In addition to antimicrobial activity, cathelicidin antimicrobial peptide plays a role in NK cell-mediated tumor growth suppression, and when secreted by neutrophils acts, as an attractant for monocytes, promoting wound healing or angiogenesis. Mouse CRAMP is implicated in adaptive immune response regulation and can interfere with TLR function via interactions with hyaluronan. Mice deficient in CRAMP are more susceptible to experimentally induced necrotic skin infection with Group A Streptococcus, urinary tract infection with uropathogenic E. coli, Pseudomonas aeruginosa infection, and meningococcal Neisseria meningitidis infection.

TRM: Slc7a2/CAT2 KO Mice

CAT2 is a membrane associated protein involved in the cellular uptake of cationic amino acids such as arginine, lysine and ornithine. CAT2 plays a regulatory role in the activation of macrophages. Arginine is a substrate for nitric oxide synthase (NOS) during the production of nitric oxide (NO). The release of NO by inflammatory cells contributes to the progression of diseases such as cancer, arthritis, inflammatory bowel disease, Crohn's disease, and atherosclerosis. CAT2 plays a role in controlling inflammation and IL-17 activation in an injury model of colitis.

Using Bacteria for Gut Health Improvement and Weight Management

Researchers at the University of California, Davis have developed a method of using bacteriocin peptides to reduce gut inflammation, improve gut barrier function, and reduce obesity in humans.

Hv1 Modulators and Uses

Researchers at UCI have engineered a class of Hv1 polypeptide modulators that selectively modulate Hv1 voltage gated channels while leaving other voltage gated channels unaffected. With no Hv1 modulators currently on the market, this class of Hv1 polypeptide modulators could provide solutions in birth control, autoimmune therapies, and tumor reduction.

A New Approach To Treat/Manage Inflammatory Bowel Disease

Researchers at UCI have developed a safe, inexpensive drug for the treatment of inflammatory bowel diseases.

Method for the detection of specific cells in bodily fluids with a small fluorescent probe

Using standard cellular biology techniques, researchers at UCI have developed a method for detecting the cellular components of blood easily, cheaply, and quickly with accurate quantification using fluorescence techniques.

Novel Protease for Oncology and Inflammatory Diseases

The technology is a novel protease that reduces the ability of cells to respond to the inflammatory cytokine Tumor Necrosis Factor (TNF). High TNF levels have been linked to rheumatoid arthritis, Crohn’s disease and many types of cancers.

Engineered Biomaterial to Prevent Endothelial Inflammation

Researchers at the University of California, Davis have developed a biocompatible material to mimic the glycocalyx, the natural layer of molecules that coats the outside of endothelial cells. This technology can be used to treat inflammation in diseases characterized by dysfunction in leukocyte-endothelial cell interactions.

Development of Methods to Inhibit IL-1β and IL-18 Production

Macrophages respond to pathogens and tissue damage via pattern recognition receptors (PRR) that sense pathogen (PAMP) or damage (DAMP) associated molecular patterns. NLRP3, a member of the Nod-like receptor (NLR) family that is induced upon macrophage activation, senses cytosolic oxidized mitochondrial DNA (ox-mtDNA) that is generated when activated macrophages are exposed to NLRP3- activating DAMPs, such as ATP, uric acid, or amyloid β, triggers IL-1β and IL-18 production and release. IL-1β and IL-18 are members of the IL-1 family of cytokines representing two of eleven members. As a whole, the IL-1 group of cytokines can induce strong inflammatory signals. Moreover, IL-1β and IL-18 are unique members because they are inactive until undergoing proteasomal cleavage by caspase-1 leading to the formation of active biological forms. Recent work has shown that NLRP3 inflammasome dependent production of IL-1β and IL-18 is involved in the pathogenesis of many devastating diseases, including cancer, Alzheimer’s disease, rheumatoid diseases and cryopyrin-associated periodic syndromes. and autoimmune diseases such as lupus or Still’s diseases. Thus, there exists a need to modulate the production of both IL-1β and IL-18.

Novel Clotrimazole Analogs As Blockers Of Intermediate Conductance Kca Channels

Researchers at the University of California, Davis, have developed a method for preparing therapeutically effective amounts of triarylmethane compounds for immunosuppressive treatment of autoimmune disorders, graft rejection, and graft or host disease.

Targeting Hyaluronan as an Immunomodulator for Treatment of Inflammatory Diseases

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and has been associated with poor quality of life and frequent complications requiring hospitalization and surgical procedures. Current therapies for IBD typically target neutralization of inflammatory cytokines, blockade of receptors, or inhibition of inflammatory cell functions. Despite current approaches, it is still difficult to control disease severity and maintain quality of life. One important phenotype of IBD that may offer an opportunity for gaining increased understanding of the disease is that up to 40% of individuals with inflammatory diseases of the colon have extra intestinal manifestations. Foremost in these extra intestinal symptoms are skin or oral disorders such as erythema nodosum, pyoderma gangreneosum and aphthous stomatitis. The presence of diseases associated with IBD at sites far from the gut support several hypotheses that IBD is a systemic disorder of circulating bone marrow derived immunocytes, a consequence of dysbiosis of the microbiome or a generalized disorder of epithelial function. Furthermore, appropriate function of the epithelial barrier is necessary to regulate the interactions between microbes and the host and maintain health.

Methods Comprising Immune System Modulation With Microporous Annealed Particle Gels

UCLA researchers have developed a novel microporous annealed particle (MAP) scaffold that acts as both a tissue growth scaffold and an immune modulatory system. The technology permits continuous, time-encoded, modulation of the immune system delivered injection/implantation of fabricated scaffold, comprised of the MAP gel technology.

Modulating IRE1a/ß Kinase for Treatment of Unfolded Protein Response (UPR)-related Diseases

This invention identifies a series of compounds which can selectively regulate the kinase activity of IRE1α and IRE1β, which are paralogous enzymes critical for the activation of the unfolded protein response (UPR) and that may have implications in cell-degenerative diseases such as diabetes, cancer, fibrosis, asthma, and retinitis pigmentosa.  

Metabolic Requirements for Alternative Macrophage Activation

UCLA researchers in the Department of Molecular and Medical Pharmacology have discovered that Coenzyme A is a targetable requirement for anti-inflammatory macrophage differentiation.

High Throughput Digital Cell Quantification Of Immune Cell Subsets Via Epigenetic Markers

UCLA researchers in the Department of Molecular, Cell, and Developmental Biology have developed a novel high-throughput method for the quantification of immune cell subtype.

3D Scaffolds For Mesoderm Differentiation

Researchers led by Benjamin Wu from the Departments of Bioengineering and Pathology & Laboratory Medicine have developed an implantable scaffolding that can create hematopoietic stem cells from pluripotent stem cells in vivo.

Identification of Novel Regulatory CD8 T Cells in Control of Inflammation in the Gut

A dynamic set of complex interactions between intestinal microbes, intestinal epithelial cells and intestinal immune cells are key in maintaining normal intestinal homeostasis as well as in the etiology of Inflammatory Bowel Disease (IBD). It is becoming clear that regulatory T cell-mediated control of inflammation is critical for the maintenance of immune tolerance in gut. Since 1970s, it has been suggested that CD8+ regulatory T cells play an important role in immune regulation of autoimmune diseases, transplant tolerance, and homeostasis of cellular and humoral immune responses. Among Treg subpopulations, an important role for Foxp3+CD4+ Treg and Foxp3- IL-10-secreting CD4+ T cells has been elucidated, while the function of CD8+ regulatory T cells in the gut has been hampered by an inability to distinguish them from conventional CD8+ T cells. Normally specific cytokines and transcription factors are the driving factors for maintaining the expression of a particular T cell phenotype.

Small Molecule Pendrin Inhibitors for Treatment of Inflammatory Airway Diseases and Diuretic Resistance

Small molecule pendrin inhibitors for treating inflammatory lung diseases.

Lentiviral Vectors Expressing FoxP3 Or IL-10 In Hematopoietic Stem Cells To Treat Immune Deficiencies And Auto-Immune Diseases

The Kohn group at UCLA has created lentiviral vectors expressing FoxP3 or IL-10 for transduction into patient hematopoietic stem cells (HSC). Successful transplantation of autologous HSCs would allow for treatment of a number of auto-immune and auto-inflammatory diseases, while avoiding complications associated with allogenic transplants or autologous T cell therapies.

Biomarker for Inflammatory Bowel Disease

Prof. Declan McCole and his colleagues at the University of California, Riverside have identified that increased levels of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) correlate to a loss of function mutation in a protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene. PTPN2 has been identified as an IBD candidate gene that protects the intestinal epithelial barrier.  Dysfunction of the PTPN2 gene, which encodes the T-cell protein tyrosine phosphatase (TCPTP) protein, contributes to alterations in the intestinal microbiome and the onset of chronic intestinal inflammation which is a symptom of IBD. Loss of function of PTPN2 has resulted in IBD-like symptoms in mice and caused the increased abundance of the intestinal pathobiont adherent-invasive Escherichia coli that binds to CEACAM6 and increases a patient’s susceptibility to IBD. Fig. 1 shows control and PTPN2-KD cell lysates with reduced protein expression of TCPTP (PTPN2) in PTPN2-deficient cells that express increased CEACAM6 protein when compared to control cells  

“CT Mucus Score” - A New Scoring System that Quantifies Airway Mucus Impaction Using CT Scans

A novel method to measure airway mucus plugging using CT images from patients with asthma or chronic obstructive pulmonary disease (COPD) patients.

Bioavailable Dual sEH/PDE4 Inhibitor for Inflammatory Pain

Researchers at the University of California, Davis, have developed a dual soluble epoxide hydrolase (sEH)/ phosphodiesterase 4 (PDE4) inhibitor for the treatment of inflammatory pain.

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