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Compositions and Methods for Treating Viral Infections

Researchers at the University of California, Davis (“UC Davis”) have developed methods for screening and targeting regions of viral genomes to identify drugs that inhibit the replication of RNA viruses.

METHODS FOR PREDICTING THE RESPONSE TO METHOTREXATE AND TREATING RHEUMATOID ARTHRITIS

Researchers at UCSF have developed methods of treating Rheumatoid arthritis and for predicting the response of patients to methotrexate. 

AUTOANTIBODIES AS BIOMARKERS FOR AUTOIMMUNE POLYGLANDULAR SYNDROME TYPE 1

Researchers at UCSF and the Chan Zuckerberg Biohub have identified multiple common autoantibody targets in APS1 patients through proteome-wide programmable phage-display.

Methods to Prevent and Treat Diffuse Large and Other B Cell Lymphomas

Professor Ameae Walker from the University of California, Riverside, Professor Srividya Swaminathan from the City of Hope Beckman Research Institute and their colleagues have developed a method for the prevention and treatment of B cell lymphomas. This technology works by systemically inhibiting expression of one form of the set of cell surface molecules that allow cells to respond to prolactin. This highly specific technology suppresses the deleterious downstream effects of prolactin that promote and sustain abnormal B cells. This invention is advantageous compared to existing technologies: all measures in mouse models and analysis of human cells suggest it is nontoxic and therefore will have significantly fewer, if any, side effects. It may also be used together with anti-psychotics that elevate prolactin. Finally, the technology includes a method for screening populations susceptible to development of DLBCL and other B lymphomas for early signs of disease. Antimaia Acts at Three Stages of B Lymphoma Development: 1) Antimaia, a splice modulating oligonucleotide (SMO) that decreases expression of the long form of the prolactin receptor, reduces the number of premalignant cells and the formation of abnormal antibody-producing cells. This also improves the symptomatology of autoimmune disease. 2) Antimaia prevents the conversion of premalignant to overt malignant B cells. 3) Antimaia kills B lymphoma cells. Antimaia works by reducing the number of long and intermediate form prolactin receptors (LF/IF PRLR) without effect on short receptors (SFPRLR). PRL, prolactin; Bcl2, B cell lymphoma 2; Myc, a proto-oncogene.

Leveraging microbiome bacteria, bacterial modulators, and novel microbial species for prevention, diagnosis, and treatment of inflammatory diseases, respiratory system infections, and premature birth

The following technologies encompass a portfolio of microbiome-centric inventions intended to address unmet diagnostic and treatment needs in the areas of inflammatory disease and respiratory system infections, including prevention in infants. 

Anti-Hla-A2 Chimeric Antigen Receptor

Brief description not available

Integrin Binding to P-Selectin as a Treatment for Cancer and Inflammation

Researchers at the University of California, Davis have developed a potential drug target for cancer and inflammation by studying the binding of integrins to P-selectin.

Modulating MD-2-Integrin Interaction for Sepsis Treatment

Researchers at the University of California, Davis have developed a potential therapeutic treatment for sepsis by modulating the interaction between integrins and Myeloid Differentiation factor 2 (MD-2).

Kaposi Sarcoma Associated Herpesvirus Gene Function and Methods for Developing Antivirals, Anti-KSHV Vaccines, and KSHV Based Vectors

The inventors present a novel strategy for achieving pathogen opportunistic pathogenesis, with broad implications for treating infectious diseases. In a comprehensive analysis of Kaposi sarcoma associated herpesvirus (KSHV), a medically important virus, the inventors discovered novel antiviral targets and gene function, and identified opportunistic factors with dual functions of regulating both the immune environment/responses and viral reactivation/replication. This discovery includes:A collection of KSHV mutants with inactivation or deletion of each of the 91 predicted open reading frames (91 mutant strains). Methods and reagents (e.g. primers) for construction of the collection of KSHV mutants. The identity of 44 KSHV essential genes, which represent potential antiviral targets (including 27 newly identified essential genes). Methods for construction of gene-inactivation and rescued mutants, and for tagging and introducing foreign genes into the KSHV genome. These approaches can be used for vector and vaccine development. Growth properties of viral mutants with inactivation of non-essential genes.Methods for screening mutants in different human cell lines.Opportunistic factors of KSHV and all other animal viruses that have dual functions as both the modulators of immune environment/response and regulators of viral reactivation/replication.   

Novel Estrogen Receptor ß (ERß) Drugs for the Treatment of Multiple Sclerosis (MS)

Prof. Seema K. Tiwari-Woodruff from the University of California, Riverside, Prof. John Katzellenbogen and colleagues from the University of Illinois have developed novel estrogen receptor β (ERβ) drugs for the treatment of MS. These novel MS drugs are specific for ERβ and have tremendous potential for the treatment of MS as well as other neurodegenerative diseases. In general, estrogens have anti-inflammatory and neuroprotective activities and clinically reduce the severity of MS and other neurodegenerative diseases. The compounds are more superior to other estrogenic drugs due to their specificity for ERβ and lack of undesirable effects such as feminization and increased risk of cancer. Fig 1: Therapeutic treatment with the UCR ERβ ligands began at peak disease (day 17) and was continued daily till day 36. ERβ ligands (blue, and orange) significantly attenuated clinical disease severity compared to vehicle treatment (red).  

Inhibitors of Bromodomain and Extra-Terminal (BET) Family Proteins as Potential Treatments for Drug-Resistant Tumors

Researchers at the University of California, Davis have developed small molecule inhibitors for use in treating drug-resistant tumors – including cancerous tumors.

A Broadly Neutralizing Molecule Against Clostridium Difficile Toxin B

Researchers at UCI have developed a family of recombinant protein therapeutics against Clostridium difficile designed to provide broad-spectrum protection and neutralization against all isoforms of its main toxin, TcdB. These antitoxin molecules feature fragments of TcdB’s human receptors which compete for TcdB binding, significantly improving upon existing antibody therapeutics for Clostridium difficile infections.

Clearance of Senescent Cells by Activation of the Immune Response

Researchers at UCSF have developed a method to selectively clear senescent cells by stimulating an immune response. Accumulation of senescent cells underlies a number of disease conditions and age-related pathologies. Current approaches to clear this cell type use senolytics, these are small-molecules that induce cell death of the senescent cells. Unfortunately, these compounds are not truly specific and affect other non-pathogenic cells. UCSF researchers eliminate these off-target effects by utilizing the body’s immune system to selectively target senescent cells for clearance. They do this by activation and expansion of certain immune cells. Stimulating the immune system to clear these cells is unprecedented in the field and offers a new therapeutic modality to treat senescence associated conditions. The technology has been fully validated in a laboratory setting.

Insulin Infusion Cannulas with Superior Performance

Researchers at UCI have developed the application of a biocompatible material to insulin infusion devices for Type 1 Diabetes to improve device strength, reduce scar tissue buildup, and increase the efficiency of insulin delivery.

Modulation of Protein Tyrosine Phosphatase Receptor Type A (PTPRA) to Treat Arthritis

Fibroblast-like synoviocytes (FLS) in the intimal lining of the joint synovium control the composition of the synovial fluid and extracellular matrix (ECM) of the joint lining. In rheumatoid arthritis (RA), FLS become aggressive and invasive, contributing to many aspects of RA pathology. FLS produce matrix metalloproteinases (MMPs) that break down the ECM, directly invade and digest the articular cartilage, promote bone erosion, and promote inflammation through secretion of interleukin 6 (IL-6), chemokines, and other inflammatory mediators. FLS are highly sensitive to the inflammatory environment present in rheumatoid joints. Growth factors, especially platelet-derived growvth factor (PDGF), stimulate FLS invasiveness. Inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF) and interleukin-I (IL-1), enhance FLS aggressiveness, pro-inflammatory features and MMP production. Targeting of molecules that control FLS invasiveness and inflammatory output is being considered an option for development of new therapies for RA.   Many signaling pathways controlling FLS behavior rely upon phosphorylation of proteins on tyrosine residues, which results from the balanced action of protein tyrosine kinases (PTKs) and phosphatases (PTPs). We found that a protein (PTPRA) belonging to a novel and currently untapped class of drug targets is present at high levels in cells lining the joints of RA patients, where we believe it promotes the aggressive behavior of these cells in joint inflammation and destruction.

Fusion Protein for Treatment of Inflammatory Diseases

Researchers at the University of California, Davis have developed a plant-based, fusion protein for use in the treatment of inflammatory diseases.

Human-Centered Drug Discovery: A Methodology To Identify And Validate High-Value Therapeutic Targets For Human Diseases

Modeling diseases as networks has helped simplify an otherwise complex web of multi‐cellular processes; however, an exclusive reliance on symmetric relationships in these networks overlooks the existence of disease continuum states and loses information relevant to pathogenesis and for the development of therapeutics. Network‐based analyses severely influenced by symmetric analyses have helped formalize Network Medicine as a field and deliver many successes, but drugs that can predictably re‐set the network in complex multi‐component diseases are yet to emerge.

Novel microbial species that promote fetal tolerogenic immunity

New therapies to prevent the development of asthma and other chronic inflammatory diseases in infants using natural bacterial modulators of fetal immune development.

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.

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