Bronchial asthma is a chronic and heterogeneous inflammatory disorder of the conducting airways with immune and non-immune etiologies. Although the underlying molecular basis of asthma is not completely understood, inflammation is a key pathological feature of bronchial asthma. The increasing prevalence in Western countries (approximately 15% of children and 8% of adults) supports the vast resources deployed to find treatments and drugs that act upon pathways not targeted in current therapies are of particular interest. (more...)

   Endophytes, microorganisms that reside in the tissues of living plants, are relatively unstudied and potential sources of novel natural products for exploitation in medicine, agriculture, and industry. Endophytic microbes, often in tropical rainforests, make compounds that have potential uses in medicine and agriculture, such as antibiotics, antioxidants and immunosuppressants. A collection of fungal endophytes in the tropical rainforest is of particular interest since it shows strong inhibitory activity toward a common pathogen of many plant species. The compound extracted from the fungal endophyte reveals strong similarities to cyclosporin A, an important immunosupressive drug. Since the discovery of cyclosporin A in 1976, it has been the principal immunosuppressive agent used in medicine. In present days, in addition to cyclosporin A, tacrolimus and sirolimus also are immunosupressants used in clinical practice and they act on T cell lymphocytes. However, all three drugs produce severe side-effects, including nephrotoxicity, beta-cell toxicity, hypertension and hyperlipidaemia.        (more...)

Together, the specificity of engineered antibodies and the diagnostic power of in vivo imaging provide a tremendous opportunity for exploring disease pathogenesis. CD8 is expressed on a subtype of T cells, known as cytotoxic T cells as well as a subset of dendritic cells. CD8+ T cells are the subject of intense research efforts, including those for developing cellular immunotherapies and for understanding tumor oncology.  The present invention describes a functional CD8-imaging agent based on engineered antibodies.  The agents have clear use in a variety of preclinical disease and immuno-therapeutic models. The ability to monitor the migration, expansion, and longevity of therapeutically transferred cells using molecular imaging technologies is of critical importance for developing immunomodulating therapies.  (more...)

 AIDS, the disease caused by the virus HIV, represents a devastating global pandemic. According to a United Nations report in 2010, HIV has killed nearly 30 million people worldwide, with over 2.5 million additional infections each year. Detecting HIV particles is critical not only to patient diagnosis, but also for basic and clinical research, the source of future therapies. Unfortunately, current methods are severely lacking. Phenotypic testing can take over a month to complete and only reports a single time point. Another system widely used for research employs cell lines that express CD4 and co-receptors at abnormally high levels, rendering results of questionable physiological relevance. Patients, physicians, and researchers alike would benefit greatly from a new method of detecting and characterizing HIV; one that is rapid, sensitive, adaptable, and most importantly, physiologically accurate.      (more...)

This invention provides microRNA therapeutics that augment blood vessel growth, which may have application for indications where it is desired to reduce or stimulate angiogenesis. Reducing or inhibiting angiogenesis may be useful for indications such as degenerative eye diseases and cancer. Stimulating blood vessel growth may be useful for treating indications such as cardiovascular, thrombotic or ischemic diseases. Cells lining blood vessels are usually among the least proliferative cell types, but this desired quiescence may be interrupted in response to growth factors during pathological neovascularization manifested in disease states such as macular degeneration and cancer. MicroRNAs are known to be key regulators of angiogenesis and specific miRNAs have been found to be effective toward these indications. (more...)

The chemokine domain fractalkine binds to integrins and this interaction is required for fractalkine signaling. The integrin binding is defective mutant acts as a dominant-negative mutant and is a therapeutic target for treating inflammatory diseases. (more...)

Systemic autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD) and psoriasis affect, in total, more than 2% of the population. It is generally accepted that the etiopathogenesis of these diseases relies on a series of stochastic events which occur in genetically prone individuals. The outcome is an impairment of the control of those immunological mechanisms which generate and perpetuate inflammation. As a consequence, self reverberating autoimmune inflammation generates both systemic and organ specific damage. Recent progress in molecular immunology has made available novel drugs, particularly biologics, which can efficiently interfere with certain mechanisms and mediators of autoimmune inflammation. These drugs are often costly and have  serious side effects.  Their efficacy, albeit remarkable, is not complete. In combination with immune-suppressants disease control is often achieved, although at a high financial and personal cost No current therapy induces permanent remission. Relapses occur when therapy is withdrawn. Hence, we have the tools to control disease in a  majority of patients but we do not have tools to maintain it.The real challenge in this field has been to evolve a novel therapeutic approach focused on immune tolerance rather than immune suppression. The unique feature of the technology developed at UCSD is that it does not suppress the immune system, instead, it utilizes this system to support its function.  (more...)

This invention uses multi-functional magnetic imaging probes to image high risk atherosclerosis and nonatherosclerotic sites such as areas of cancer, infection, immunological conditions and inflammation. The invention incorporates the use of micelles containing the manganese to which are attached to oxidation specific antibodies. This multi-functional particle is injected intravenously and will enter an area of atherosclerotic plaque in the vessel wall or other site of inflammation (primary or metastatic cancer, liver disease, arthritis, Alzheimer's, macular degeneration, etc.) and the antibody will direct the micelle with the manganese to an oxidation specific epitope. Once it binds, the micelle will be taken up into a macrophage. Lysosomal enzymes in the macrophage will then cleave the manganese off the micelle which greatly enhances its relaxivity, which is a key part of the invention, that then allows the manganese to be detected by molecular bio-magnetic resonance imaging (MRI).The unique aspect of this invention is the fact that manganese is normally not easily visible by MRI when it is complexed to another carrier. However, manganese is visible to MRI when it is in a free state. Because free manganese cannot be injected for specific localization, it must be complexed to a carrier that will do two things: 1) deliver the manganese to a specific targeting area, which in this case is via the oxidation specific antibody and 2), have a mechanism by which the manganese is released to be seen with MRI techniques. This invention has these two novel aspects of using a targeting agent to deliver the manganese and through the natural pathophysiology of atherosclerosis allowing the manganese micelle to be taken out by macrophages and subsequently released in the macrophage. This results in a macrophage specific imaging. Since macrophages are associated with unstable atherosclerotic lesions and all areas of inflammation, this technique may allow a novel approach to image macrophage activity and therefore lesions that would predict higher cardiovascular risk. (more...)

The current gold standard for disease monitoring in the clinical treatment of asthma are flow rate and lung volumes readings, which are combined in spirometer. When another important biochemical indicator fluctuates significantly, this indicates inflammation of the airways.  While these disease monitoring data points can currently be obtained in a clinical setting on a one-off basis, it would be very useful if they were available on an ongoing basis, and ideally also in a home setting.  If spirometry and specific biochemical levels could be monitored in tandem on an ongoing basis, this would provide predictability of an asthma attack.   In response to this challenge, investigators at University of California at Berkeley have developed an inhaler based asthma attack predicting spirometer-biochemical sensor.   This innovation combines these two key clinical indicators on an inhaler, which is used regularly and frequently by asthma patients.  The asthma attack predicting sensor has an inlet for spirometry measurements where the air flows into one chamber.  Here, biochemical levels and airflow are quantified. The asthma attack predicting sensor also has a pressure sensor and signal transducer for the flow rate measurements.  All information can be transmitted wirelessly to the clinician.  An outlet for the inhaler medication to be released is also provided, just as in a regular inhaler.  The first commercial use of the asthma attack predicting sensor will be to monitor the severity in the occurrence of an asthma attack in children ages 8-12 with severe asthma.  The broader usages will be to provide information to clinicians for the personalization and predictability of an asthma attack in all asthma patients. Potentially, anyone with asthma, regardless of the severity and age of the user, would find the device beneficial in tracking medical information for personal reasons or to provide the information to their clinician. (more...)

Fatigue, blindness, deafness, and atrial fibrillation can individually affect a broad range of people and cause a wide range of effects on their quality of life. Although these conditions may appear to be unrelated, they may have a similar connection. The diagnosis and confirmation of these diseases and conditions will allow for proactive treatment and treatment monitoring.Researchers at the University of California, Irvine have discovered a genetic connection between the seemingly unrelated conditions of fatigue, blindness, deafness, and atrial fibrillation. Their discovery can be used to aid in the diagnosis, confirmation of the diagnosis, and treatment of the disease. Additionally, this discovery can be used to improve the performance of healthy individuals. (more...)

Among all solid organ or tissue transplantations, corneal transplantation is the most successful, with a 2-year survival rate of 90% in patients with inflamed and avascular (low-risk) graft beds.  Unfortunately, the rejection rate reaches as high as 50-90% when the grafting is performed on inflamed and highly vascularized (high-risk) corneas. Many patients who are blind as a result of corneal diseases fall in this category after traumatic, inflammatory, infectious, or chemical damage. Such patients are not considered as good candidates for transplantation surgery and have to give up their hope for vision restoration. To address these challenges, investigators at University of California at Berkeley have developed a technical strategy using a combined blockade of VEGFR-3 and VLA-1 that markedly improves high-risk corneal transplant transparency and survival. This strategy suppresses lymphatic vessels in grafted corneas. It provides a new and powerful strategy to combat high-risk corneal transplant rejection. The strategy may also be used to treat low-risk transplant rejection and other immune-or lymphatic-related diseases. It can be locally or systemically administered. (more...)

The Human Immunodeficiency Virus (HIV) has evolved a number of mechanisms of evading the human immune system.  One way is through a high level of mutation, which makes it difficult to develop a vaccine that stimulates protective immunity against all of the different HIV variants.  Therefore, scientists are searching for a general surrogate maker that could be used to target any HIV-infected cell regardless of its mutational status. In this regard, scientists have recently focused their attention on so-called cryptic peptides of HIV.  Cryptic peptides are non-functional HIV proteins that are produced due to translational errors that occur in HIV-infected cells.  Because these cryptic peptides are commonly produced and then presented on the surface of the HIV-infected cells, it is thought they may be good surrogate markers and targets for any HIV-infected cell. (more...)

Human Immunodeficiency Virus (HIV) has evolved a number of mechanisms of evading the human immune system.  One way is through a high level of mutation, which makes it difficult to develop a vaccine that stimulates protective immunity against all of the different HIV variants.  Therefore, scientists are searching for a general surrogate marker that could be used to target any HIV-infected cell regardless of its mutational status. In this regard, scientists have recently turned their attention to the APOBEC machinery in HIV cells.  APOBEC proteins are human proteins that modify genetic material of viruses so that they are unable to produce proteins essential for viral survival.  Remarkably, HIV evades the APOBEC defense by making a protein called Vif that re-routes APOBEC proteins to proteosomes for destruction thereby reducing APOBEC's protective functions.  However, this activity also increases the presentation of APOBEC antigens or peptides on the cell's surface. APOBEC peptides may be good candidates for surrogate HIV markers simply because they are present on the surface of all HIV-infected cells.  In addition, in order for HIV-infected cells to stop displaying APOBEC peptides on their surface, the virus would need to evolve mutations in the region coding for the Vif protein that re-routes the APOBEC proteins.  This would make the virus vulnerable to the defenses mediated by the functional APOBEC proteins.  This phenomenon should result in dual pressure on the virus that should slow or prevent the evolution of viral resistance to these T-cell responses. (more...)

BACKGROUND: Natural Killer T-cells (NKT cells) are a growing area of preclinical and clinical research, and modulation of these cells has therapeutic applications in various diseases with immunological, infectious, or oncologic components. DESCRIPTION: Investigators at UCSF and Harvard have identified, isolated, purified, and characterized a novel chemical composition – a glycolipid molecule, from a prominent commensal bacterium. The glycolipid is an analog of a known synthetic class of compounds that are known to activate natural killer T-cells. This new glycolipid compound is also a close analog of a previous clinical candidate for cancer and viral infections, and a current clinical candidate for autoimmune disorders, including graft-versus-host disease. However, the other known NKT activators are synthetic and are thus non-physiological. By contrast the new glycolipid is a fully natural glycolipid produced by resident microbes of the human GI tract. The investigators have demonstrated the ability of the new glycolipid to activate NKT cells and classical NKT-cell cytokine response in cellular experiments (via administration to immune cells) and in vivo (via application of glycolipid-pulsed dendritic cells to conventional mice, and variable expression of the relevant synthetic pathway in gnotobiotic mice).  Interestingly, the glycolipid appears to have a subtle but significant difference in in vitro affinity for NKT cells as well as a different cytokine activation profile from known, synthetic NKT activator. Our study implies that the co-evolved human gut microbiome might specifically produce this physiological glycolipid as a natural ligand that modulates the NKT subset of immune cells relevant to pathogen response and autoimmune disease. Given that the compound is significantly different in structure and activity than the previously studied compounds, this new glycolipid and the surrounding chemical space should be useful as therapeutics as well as research tools. (more...)

Human skin is exposed to a multitude of chemicals on a daily basis, many of which can be hazardous or induce an irritant reaction.  While there is strict government regulation in regards to screening of these chemicals, this testing has typically relied on the use of animal models.  However, in recent years the use of in vitro screening methods has become more prominent, with reconstructed human epidermis models being a preferred technique.  Unfortunately, this approach is both time-comsuming and expensive, as well as being difficult to develop as a high throughput screen. (more...)

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Asthma, a chronic inflammatory disease of the lung, affects an increasingly larger population every year and presents a major public health problem in terms of morbidity and cost. The cause and mechanisms of asthma and allergic diseases are not yet understood. As the spontaneous development of asthma in a non-human animal is next to impossible, the ability to engineer mouse models of the disease remains critical to the understanding and treatment of the disease. (more...)

A system using nanotechnology to synthetically replicate the body's immune function for uses in body fluid filtration, stimulation of immune system, therapeutics and diagnostics. (more...)

Background: In 2009, 300 million people worldwide suffered from asthma and the incidence continues to increase. Current therapies lead to global suppression of the immune system rather than specifically treating asthma symptoms and could result in unwanted side effects. Beta agonists are the most widely used clinical treatment to reverse airway narrowing and shortness of breath caused by smooth muscle dysfunction. However, there is conflicting evidence as to the long-term safety of their use, with some reports of increased mortality in patients who rely heavily on their use. Therefore, innovative therapies are needed that specifically target and reverse airway constriction and rapidly alleviate shortness of breath resulting from acute asthma exacerbations without leading to adverse effects. Technology Description: Researchers at UCSF have identified a novel protein that could be used as a therapy to reduce shortness of breath in asthma. The protein has been shown to target a molecular pathway that controls smooth muscle contraction and thereby affects airway constriction. In both short-term and chronic allergen challenge models, mice deficient in this protein developed more severe asthma as shown by increased airway hyperresponsiveness. The therapeutic effects of the protein on airway smooth muscle contraction are evident in a mouse model of allergic asthma where after in vivo induction of asthma, tracheal rings are isolated from mice to measure their contractile response to agonists in vitro. The administration of this protein to tracheal rings reduces the force of contraction and the degree of airway narrowing. Addition of the protein also specifically acts to reduce asthmatic symptoms only after asthma induction, thus reducing the risk of potentially hazardous adverse effects. Thus, this protein holds promise as a novel and safe quick-relief therapeutic for asthma sufferers. Current and future studies are focused on validating these results by therapeutically administering the protein in in vivo mouse models, mapping the protein domain responsible for therapeutic action, screening for small peptides that reproduce the effects of the whole protein, identifying the molecular target of the protein, and testing the combined effect of the protein with beta agonists. The identification of a peptide with specific action could decrease any potential side effects that are present in the whole protein. Closely related proteins will also be studied for their action in asthma models. After validation in mouse models, the efficacy of the protein therapeutic will be evaluated in human subjects with asthma. (more...)

Immunostimulatory nucleic acid molecules (ISS) are DNA sequences, originally found in bacteria, that enhance an immune response by activation of specific cells and proteins, including cytotoxic T cells (CTLs). These activated CTLs recognize and destroy cells in the body that have been altered, e.g. by infection with a virus or by transformation into cancer cells. However, individuals who are deficient in helper T cells may not derive the benefit of ISS stimulation. (more...)

  Background Over a dozen companies have pursued the development of TGF- β modulators for the treatment of cancer, pulmonary fibrosis, and renal disease. However, the near-ubiquitous presence of the three mammalian TGF- β isoforms across tissue types, as well as its complex and diverse effects on downstream signaling pathways, mean there is a high likelihood that chronic global suppression of TGF-β will result in undesirable off-target effects. An agent effecting tissue and disease-specific mitigation of TGF- β activity while sparing much of its contribution to normal cellular function would be of extremely high therapeutic value for a wide range of inflammatory, fibrotic and neoplastic diseases.   The integrin family of cell surface receptors are emerging as promising targets for tissue type-selective modulation of TGF- β. Because TGF- β activation in a given tissue type requires association with a specific integrin, it is believed that targeting such interactions will lead to effective therapeutics while avoiding many of the possible systemic effects of indiscriminate TGF- β suppression. In mice, conditional deletion of avb8 blocks airway inflammation and fibrosis in COPD and asthma models and can completely inhibit experimental autoimmune encephalitis. In human biospecimens, activation of TGF- β by avb8 has been directly implicated in both fibrotic and inflammatory processes of the airway in COPD.  Until now, no chemical, small molecule, or high affinity antibody agent was available that selectively blocks the interaction of TGF- β and integrin avb8.                                                                            Description UCSF investigators have developed the first mouse anti-human neutralizing monoclonal antibody that prevents the binding of two TGF- β isoforms to integrin avb8. This is the sole agent of any type that selectively targets these associations, without which TGF-b activation in vivo is severely compromised. UCSF investigators have characterized the target epitope of the antibody. In vivo, this antibody blocks airway inflammation in transgenic mice expressing only human and not mouse avb8. Short-term safety tests show no deleterious effects using high-concentrations of the antibody (7mg/kg). Animal model safety and additional efficacy tests are underway in humanized mice expressing human avb8.   This antibody offers several distinct advantages over current TGF- β modulators. First, the antibody only inhibits the activation of the TGF-b1 and b3 isoforms, sparing the neutralization of TGF-b2. The TGF-b1 isoform is widely considered to account for the majority of the disease-related biology of TGF-b.  Second, the specificity for cells expressing only the avb8 integrin isoform decreases off-target effects such as autoimmune responses, rapid-onset atherosclerosis, and carcinoma development. Third, the antibody selectively disrupts the binding of TGF- β to avb8 in a way that does not influence general cell adhesion properties mediated by this interaction, further minimizing non-TGF-b-related effects. (more...)

During their lifetime, some form of cancer affects more than 40 percent of the U.S. population. It is known that the catch-all term “cancer” includes a variety of diseases with varying etiology and prognoses. It is also known that the progression to metastasis radically changes treatment options. Despite the trend toward better understanding of the nuances of various types of cancer, the critical aspect of effective therapy remains early detection. An early indicator of cancer would allow physicians to proactively test and choose appropriate treatments, before disease progression has ruled out the most effective, early options. (more...)

It has been shown recently that in addition to their classical role in desensitizing G protein coupled receptors (GPCR’s), beta-arrestins can act as signaling molecules themselves. Thus, it is now widely held that GPCR’s are able to signal through parallel G-Protein and beta-arrestin pathways. Next generation GPCR therapeutics will be advanced by fine-tuning the actions along these pathways. GPCR ligands that preferentially activate the latter pathway are called beta-arrestin “biased” agonists. Different biological responses have been observed with such beta-arrestin biased agonists, compared with traditional GPCR therapeutics designed to activate G-proteins. (more...)

Although liposome delivery vehicles are acknowledged to improve options for drug delivery, they are inherently unstable and prone to fuse into larger aggregates. This fusion is particularly limiting for dermatologic applications because the fused liposomes (>100 nm) are unlikely to transport through the skin. Molecules, such as polyethylene glycol (PEG), can prevent fusion and enhance in vivo circulation lifetime. However, because PEG also limits fusion with bacterial membranes, it has marginal utility for dermatologic applications. The ability to stabilize liposomes against fusion until delivery to the desired site of action would significantly enhance efficiency and efficacy for transdermal drug delivery and improve processes for manufacturing and storage as well. (more...)

The immune response plays a critical role in protecting humans and animals from infection and the development of tumors. Compositions that increase the immune response (adjuvants) are therefore valuable for improving vaccine efficacy and the control of tumor growth and metastasis. Novel combinations of molecules that are immunostimulatory have been discovered. Certain of these adjuvants have been used to treat a variety of tumor types in mouse models and the results demonstrate dramatic reductions in tumor size and increased survival rates. Additionally, a combination of the molecules has been tested as an adjuvant for an anti-infective vaccine and has produced improved protective effects. This technology is simple, inexpensive, and has broad potential utility for improving existing vaccines against a variety of microbial infections and for improving immunotherapeutic approaches for treating cancer. (more...)

TCL1 is a protooncogene overexpressed in many mature B cell lymphomas. TCL1 is also expressed in precursor T cells and absent by the CD4+ CD8+ stage of thymocyte development. In B cells, TCL1 is first expressed in pro-B cells, and is completely absent in memory B cells and plasma cells. (more...)

Small peptides are gaining attention from the pharmaceutical industry as hundreds of peptides are in development or in clinical trials for a variety of diseases. Many pharmaceutical small peptides are inspired by natural antimicrobial peptides (AMPs). In particular, theta defensins, natural AMPs found in primates, have been studied extensively as prototypes of pharmaceutical drugs against HIV infection and other sexually-transmitted diseases (STDs). Previously, UCLA Researchers have discovered two human theta-defensin genes and synthesized retrocyclins 1 and 2 based on the gene sequences. Since retrocyclins 1 and 2 are active against HIV-1, HSV-1 and HSV-2, the researchers have been using them as platforms to develop smaller analogs with improved pharmacotherapeutic properties. (more...)

Aging is accompanied by a dramatic decline in immune functions involving both B and T cells. Clinical findings of increased morbidity and mortality following infections, higher incidences of cancer, and diminished antibody responses to specific vaccines are examples of immunologically-based medical problems of the elderly. However, despite a large body of research on the nature of these immunological deficits, there is no known mechanism that explains the progressive decline of immune competence with age. Nor is there a reliable biomarker to identify which subset of chronologically old individuals are at risk immunologically. (more...)

Antiphospholipid antibodies (aPL) are associated with thrombosis, spontaneous abortion, and antiphospholipid syndrome (APS). aPL antibodies recognize various phospholipids, phospholipid-binding plasma proteins and/or phospholipid-protein complexes. The plasma protein 2-glycoprotein I ( 2GPI) is recognized as one of the major autoantigens in APS. Other important autoantigens associated with APS include cardiolipin (CL) and the serine proteases thrombin, activated protein C, and plasmin. (more...)

UCLA investigators have identified a use for bacterial lipopeptides as a potent inducer of IL-12 production and resulting type 1/Th-1 T-cell response. The technology encompasses a broad range of lipoproteins of defined structure that can be administered to a subject to trigger type1/Th1 T cell response required for cell-mediated immunity in the context of infection, autoimmune disease or cancer. For example, and of current interest, the lipoprotein may be used as a topical agent for the treatment of skin infections and cancer, in which Th1 responses are required for host defense. Since this lipoprotein activates Toll-like receptor 2, it has anovel mechanism of action. (more...)

Dendritic cells (DC) are a group of professional antigen presenting cells (APC) that provide a central stimulus for the generation of cell-mediated responses against foreign antigens. Dendritic cells are ubiquitously distributed throughout the body, where they pick up antigens, process them, and migrate to T-cell enriched areas of lymphoid tissue to activate corresponding antigen-specific T-cell clones.1 A major limitation in the human response to foreign challenges, including infections and tumors, is the limited number of DC and their suppression in individuals suffering from these conditions. As a result, patients often fail to respond to vaccines that might otherwise be effective.Previous in vitro data indicated that granulocyte-macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4), when used in combination, induce precursor cells, such as CD34+ stem cells and monocytes, to mature into dendritic cells. These cells were classified as DC by their expression of cell surface markers characteristic of DC cells (CD83, CD40, CD86, CD11c, etc.), by their ability to take-up and process antigens, and by their ability to stimulate the proliferation of T cells in an antigen-specific manner. The strategy of using GM-CSF AND IL-4 to enhance the number and/or function of antigen presenting cells (including dendritic cells) in the blood, tissues and lymphoid organs of patients may be employed as a mechanism to improve the immune responses of individuals with a suppressed immunity. Therefore, this method has implications in treating conditions such as cancer, infections, AIDS, malnutrition and shock. Cytokine therapy using GM-CSF and IL-4 may further be implemented into immunization and vaccination strategies for infections that respond poorly to conventional vaccine approaches. Examples of these indications include AIDS, pneumonia, and tuberculosis.This cytokine combination therapy produced promising tumor responses in Phase I testing and is currently being tested in Phase II studies in patients with prostate cancer. Additional preclinical testing is ongoing to optimize combination therapy with vaccines, to better evaluate the form and function of the dendritic cells generated, and to evaluate the use of combination cytokine therapy as a mechanism for harvesting DC for use in the production of cell-based vaccines. (more...)

IgA is a polymeric effector molecule of the immune system that mainly acts at mucosal surfaces and is highly resistant to extreme pH conditions, whereas IgG is monomeric and acts in the blood at a narrower pH range. IgG is known for its potent complement activation and, in contrast, IgA is unable to fix complement. Combining the characteristics of IgA and IgG into a single immunoglobulin molecule may produce more effective therapeutic agents. (more...)

UCSF investigators have identified a novel endogenous agent that activates the Aryl Hydrocarbon Receptor. (more...)

Matrix metalloproteinases (MMPs) are a class of zinc-dependent hydrolytic enzymes that function in the degradation and restructuring of extracellular proteins. Overexpression of MMPs has been associated with a variety of diseases, including cancer, arthritis, and cardiovascular disease. Commercialization of MMP inhibitors (MMPi) has not been successful, as the inhibition of MMPs systemically has resulted in adverse events such as musculoskeletal syndrome. The researchers have approached this problem by developing prodrug MMPi or "proinhibitors" that are triggered in a localized fashion, minimizing the systemic effects of the drugs. A protected zinc-binding group was used to develop the proinhibitor. The researchers demonstrated that it is possible to protect the MMPi, activate it through an enzymatic reaction, and inhibit MMPs in a controlled manner. The ability to create MMP proinhibitors may provide a new approach to MMPi therapy of disease. (more...)

UCSD researchers have identified a novel method to inhibit I-kappa-beta Kinase (IKK), by targeting a particular residue in its catalytic domain. Inhibition of IKK downregulates NF-kb, the major orchestrator of the inflammatory response. This method can be used to screen candidate compounds targeted at IKK and also as a tool to design new anti-IKK compounds. This invention also provides the mechanism by which cyclopentanone prostaglandins (cyPG's) act to inhibit the catalytic activity of IKK. (more...)

UCSD researchers have identified a key activity required for the maturation of murine B cells and antibody production. This activity is also required for the formation of secondary lymphoid organs (i.e. spleen and lymph nodes). Genetic studies with deletions and "knock in" mice have shown that deletion of this activity does not interfere with T cell mediated immunity or innate immunity. This invention provides a unique target for preventing antibody-mediated pathologies, from transplantation rejection to autoimmune diseases. Additionally, this invention can also provide a novel strategy for inhibiting B cell tumors, including chronic lymphocytic leukemia. (more...)

UCSD researchers have discovered that gene therapy using agents that enhance apoptosis can suppress arthritis. This treatment decreases joint inflammation, cytokine production and metalloproteinase gene expression. Using gene-therapy approaches to block key kinases, we have developed a strategy for treating patients using intra-articular therapy. (more...)

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Certain pathogens, such as Bacillus anthracis (“Anthrax”), Yersinia pestis (“Plague”), Salmonella and Shigella (“Bacillary dysentery”), among others, attack the host by killing its macrophages, and thereby evading detection by its immune system. This phenomenon can prove even more deadly when it occurs in conjunction with a viral infection, in that the immune system may not respond to either pathogen if macrophages are eliminated. UCSD researchers have discovered the mechanism underlying this pathogen-induced macrophage apoptosis, and have developed an approach to protect the macrophage. This protection can boost the immune system so that it can better fight infections, particularly dual infections involving both bacteria and viruses. (more...)

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Osteoarthritis is the most common form of arthritis and affects millions of people. It is a debilitating, progressive disease of the joints characterized by the loss of cartilage tissues. So far, the underlying mechanism of disease is still not resolved. Current therapeutic approaches to treating osteoarthritis largely focus on pain relief and improving (or at least maintaining) mobility and include analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, corticosteroids and viscosupplementation. The nonpharmacological options include physical therapy, exercise, body-weight management, orthotics and surgery. Nevertheless, these treatments are insufficient and may be associated with unwanted side effects. (more...)

Innate and adaptive immunity contributes to the pathogenesis of rheumatoid arthritis (RA) and other human autoimmune disorders by generating and maintaining inflammation, which leads to tissue damage. Recent therapies target innate immunity with a non-specific suppression of the immune system. This approach, albeit with remarkable effects, is limited by cost and side effects, due to a generalized immunosuppression and subsequent increased occurrence of infectious diseases. The real challenge in this field has been to evolve a novel therapeutic approach focused on immune tolerance rather than immune suppression. (more...)

Inflammatory bowel disease (IBD) consists of a group of chronic gastrointestinal inflammatory disorders with unknown etiology, including ulcerative colitis (UC) and Crohn’s disease (CD). Immunosuppressive and anti-inflammatory agents in high maintenance doses are the principal drugs used in the therapy of IBD. However, about 20-25 percent of patients with UC fail to respond to this intensive therapy and are therefore referred to surgery. In general, patients with CD are even less responsive to medical therapy and usually do not respond to surgical treatment. These unresponsive patients are in need of effective treatments. (more...)

Matrix Metalloproteinases (MMPs) are zinc containing hydrolytic enzymes that are able to degrade extracellular matrix components such as collagen. MMP’s have been implicated in a variety of diseases, including cancer, arthritis, inflammatory disease, and heart disease. Despite intensive research and clinical testing of MMP inhibitors, the only approved MMP inhibitor is a tetracycline for the treatment of periodontitis. UCSD researchers have developed a novel series of organic compounds that are potent inhibitors of MMPs. While most MMP inhibitors in development are based on small peptide mimetics that chelate the zinc ion using a hydroxamic acid moiety, the UCSD researchers designed a novel class of zinc-binding groups (ZBGs) by rational drug design. The binding mode of the ZBGs was optimized using structural, spectroscopic, and computational studies of the compounds bound to an inorganic zinc model complex for MMP’s. These new inhibitors are up to 700-fold more potent than acetohydroxamic acid in MMP binding assays and are expected to have better oral availability and pharmacokinetics when compared with hydroxamate-based compounds. These ZBG inhibitors have commercial applications in drug design against MMP’s and other metalloproteins related to human disease, such as histone deacetylases. (more...)

Although algorithms and chemistries for developing new therapeutic entities are constantly evolving, none can replicate the path and novelty of natural selection over eons of time. Inventors at the Scripps Institution of Oceanography have engaged their fleet of research ships to cull the oceans for marine organisms from which new compositions are isolated.  Using a variety of culture systems, selective fractionation and bioassays, two, distinct classes of compounds, isolated from actinomycetes, have demonstrated potent anti-tumor activity and considerable selectivity toward some cancers. One class of compounds, the ammosamides, are unique molecules that target a previously untargeted intracellular pathway. It is anticipated that proprietary methods and naturally evolved compositions may yield therapeutics that are significantly differentiated from those developed by limited iteration of pre-defined platforms. (more...)

The detection of retrovirus is potentially of great importance both for diagnosis of numerous serious diseases and for monitoring retroviral-based gene therapy. However, since it is difficult to ascertain whether or not a given retrovirus may be present in a patient, the identification of diseases with possible retroviral etiology has not been straight forward and application of retroviral gene therapy techniques has been inhibited. In the case of rheumatoid arthritis, for example, the disease has been intensively investigated, yet its origins remain unresolved. Many researchers hypothesize that rheumatoid arthritis is caused by several viruses, including retroviruses. There have been reported links to retroviruses to other diseases but such links have usually been difficult to confirm These difficulties are due to the uncertainty of reliably detecting reverse transcriptase activity (by PERT for example) over background for cellular enzymes (such as telomerase). Assays such as electron microscopy visualizations and immunofluorescent probing methods are also not useful due to their low sensitivity. (more...)

Binding of autoantibody to the senescent cell membrane is a major physiologic pathway for removal of senescent red-blood cells (RBCs) from the circulation. Autoantibody to senescent RBCs is present in the plasma of all individuals and functions to limit RBC survival. In disorders characterized by shortened RBC survival, such as autoimmune hemolytic anemia, thalassemia, sickle cell anemia, and the anemia of chronic disease, this autoantibody may further exacerbate the anemia. Removal of autoantibody to senescent RBCs may provide a means to prolong RBC survival and reduce the need for transfusions. (more...)

Target-selective drug delivery remains a challenge for various therapeutic applications and particularly for cancer. Current targeting strategies include formulation and encapsulation for preferential release in the acidic tumor environment as well as covalent conjugation via linkers sensitive to pH, to oxygen levels, or to disease-specific enzymes. These approaches have been limited by: Stringent requirements on linkable drugs and carriers.Inflexible rates of release.Insufficient target/tumor-specificity of relevant enzymes. (more...)

Integrins are found throughout the animal kingdom where they play important roles in cell adhesion, migration, proliferation, and survival. In humans, integrins play critical roles in development. Aberrant activation is implicated in several disease states, including cancer and heart disease. Thus, drugs aimed at disrupting this specific interaction could lead to therapies for these conditions. (more...)

UCSF investigators have discovered the anti-inflammatory effects of two naturally occurring human proteins. (more...)

BACKGROUND: Vaccine targets for prostate cancer have generally been identified either by tissue specific expression in prostate cancer or by assessing immune responses in cancer patients. However, UCSF investigators have taken a novel approach to identify the targets of an immune response in patients who are either responding or not responding to an immune-based treatment (anti-CTLA4 antibody) in a clinical trial at UCSF. CTLA4 blockade with antibody treatment can augment endogenous anti-tumor immunity in animal models and is being developed as an immunotherapy for cancer patients. Defining the antigen-specific responses induced by this treatment can lead to immunological identification of therapeutic targets that may be relevant in prostate cancer patients. These studies provide a unique opportunity to determine the antigen-specific responses that are relevant for immune-mediated clinical responses in prostate cancer, can provide opportunities to predict which patients may respond to therapy, and can provide novel approaches to prostate cancer treatment and vaccination. DESCRIPTION: UCSF investigators found that immune-mediated clinical responses to CTLA4 blockade is seen in the absence of a specific vaccination, suggesting that endogenous antigen-specific immune responses can be potentiated through this treatment. By focusing on immune responses unique to those patients that responded to immunotherapy, the UCSF investigators were able to identify candidate antigens that correlated with clinical outcome in prostate cancer patients. In addition, a patient’s immune response to the prostate cancer-associated antigens can be used as a diagnostic assay to determine the likelihood that an individual having prostate cancer will exhibit a clinically beneficial response to an immunomodulatory treatment. Furthermore, targeting these antigens with antibodies and/or vaccination may lead to novel therapies for prostate cancer. One antigen in particular has shown promise because it is expressed at a higher intensity in prostate cancer patients and in prostate cancer cell lines compared to other previously described antigens. Kaplan-Meier survival curves for tumor challenge were plotted for C57BL/6 and FVB mice (5 control and 5 test mice per mouse model) that were immunized with a mouse homolog of the particular antigen. The mice were challenged with Tramp cells or Myc-Cap prostate cancer cells respectively. Immunization with the novel antigen induced anti-tumor responses in both models of prostate cancer. (more...)

Abnormal development of lymphoid tissue plays a critical role in many autoimmune diseases, such as rheumatoid arthritis and Graves disease. In addition, the migration of lymphocytes into diseased lymphoid tissue facilitates the progression of diseases such as AIDS. UCSF researchers have identified a pathway, involved both in the development of lymphoid tissue and in the migration of lymphocytes into lymphoid tissue, which is a potential target for screens for therapeutics to treat these diseases and other immune disorders.The B-lymphocyte chemoattractant (BLC/BCA1), through its interaction with the G-protein coupled receptor BLR1/CXCR5, is important for the migration of B-cells and a subset of T-cells and macrophages into lymphoid follicles. Recent investigation by UCSF researchers has proven that the BLC/BLR1 pathway is essential for B-cell migration to the spleen and lymph nodes, for the development of lymph nodes and Peyers patches, and for the establishment of a positive feedback loop with lymphotoxin Lta1b2 to mediate follicular dendritic development and persistent BLC expression. This work and additional studies at UCSF suggest that the interaction between BLC and its receptor, BLR1/CXCR5, may be a useful target for modulation of the normal and ectopic development of lymphoid tissue as well as lymphocyte migration. (more...)

Thrombin is an enzyme in the blood that plays a key role in platelet formation during injury. While blood coagulation is essential for a surface wound, platelet activation underlies various pathological situations such as unstable angina pectoris, myocardial infarction and stroke. Thrombin is mediated by protease activated receptor-1 (PAR-1) which is expressed in the nervous system and in platelets. Once activated by thrombin, PAR-1 induces rapid and dramatic changes in cell morphology that is controlled by a series of localized ATP-dependent reactions. (more...)

This invention is an animal model and various cell-based models to determine nociception, pain transduction, and pain threshold. Researchers at the University of California, Irvine, discovered that overexpression of voltage-gated calcium channel alpha-2-delta-l subunit in neural tissue, and especially increased expression in spinal cord and dorsal root ganglia in transgenic mice, correlates in vivo with typical nerve injury-induced nociceptive responses to innocuous mechanical and thermal stimulation (tactile allodynia and thermal hyperalgesia). Significantly, such transgenic animals can be used to investigate nerve injury-induced neuropathic pain without inflicting nerve injury to the animals, which often interferes with test results. Similarly, neural cells obtained from such transgenic animals or neural cells transformed by overexpressing the alpha-2-delta-l subunit exhibit physiological parameters remarkably similar to those of neural tissue obtained from animals thought to have nerve injury-induced neuropathic pain. (more...)

Mgat5 is an enzyme that glycosylates T-cell receptors to modulate T-cell activation and autoimmune response. Mgat5 Null PL/J Mice were developed as part of a study performed by scientists at Mount Sinai Hospital and the University of California, Irvine to establish an understanding of the role of Mgat5 modified glycans in the regulation of autoimmunity. (more...)

CRAC stands for Ca2+-Release Activated Ca2+. When Ca2+ from the endoplasmic reticulum (a major store of Ca2+) is depleted, a CRAC channel, is activated to slowly replenish the endoplasmic reticulum. The CRAC channel is critical to the activation of T lymphocytes, mast cells and other hematopoietic cells, as it provides the primary route for the influx of calcium into these cells. Inhibition of the CRAC channel could, therefore, provide one of the most direct means of modulating the immune response for the treatment of multiple diseases and disorders. (more...)

An epidemic of metabolic diseases including type 2 diabetes and obesity is undermining the health of people living in industrialized societies. There is an urgent need to develop innovative therapeutics. (more...)