Leading Role in Immunology
Because of the immune system’s complex development in the body and its ability to both provide protection from and cause fatal disease, efforts to understand and regulate its action pose a crucial challenge to biomedical research worldwide.
Few institutions rival UCSF’s research capacity in immunology – an effort already known for clarifying key steps in the formation of the immune defense system and for devising strategies to modify and control immune reactions to treat and prevent disease.
Ophthalmoscope image of the retina of a patient suffering from lupus.
UCSF immunologists have pioneered new approaches to induce the immune system to tolerate transplanted organs, and to dampen its errant responses that cause autoimmune diseases. Researchers also have identified a number of genes that affect both vulnerability to immune-related disease and the ability to combat diseases as deadly as cancer. Support for the research program includes the Immune Tolerance Network (ITN), an international consortium of leading scientific researchers and clinical specialists who focus on testing new therapies to promote immune tolerance.
“UCSF’s immunology research enterprise is of extraordinary quality,” says Arthur Weiss, MD, PhD, professor of medicine and chief of the Division of Rheumatology. Weiss himself discovered how certain enzymes control signaling within the immune system – discoveries that now form the basis for patient clinical trials to treat both leukemia and rheumatoid arthritis.
“The breadth and depth of research here are almost unmatched,” Weiss says, both in probing molecular mechanisms that control the immune response and in advancing understanding of a range of diseases, from infections to autoimmune diseases and cancer.
UCSF investigations include:
- Lindsey Criswell, MD, MPH, professor of medicine and an investigator in UCSF’s Institute for Human Genetics, is leading a research collaboration that has identified genes partly responsible for a person’s risk for rheumatoid arthritis and lupus. Using genome-wide techniques to screen for gene-environment interactions, the team also found a relationship between exposure to tobacco smoke and two specific genetic risk factors.
- Immunology and infectious disease specialist Richard Locksley, MD, directs the UCSF Sandler Asthma Basic Research Center. The center brings together a team of immunology researchers focusing on underlying causes of, and potential treatment targets for, a disease that has reached epidemic proportions in some areas. Asthma scientists have identified genetic risks and unsuspected asthma triggers, and now are launching one of the first focused research programs to study the immune system as it functions within the airways.
- Immunobiologist Jeffrey Bluestone, PhD, UCSF executive vice chancellor and provost, who co-founded the ITN, is a prominent leader in research to modify the response of key immune molecules in order to reduce harmful autoimmune attacks and boost the immune system’s protective capacity. Clinical trials sponsored by both ITN and the National Institutes of Health are testing these strategies in type 1 diabetes patients and organ transplant recipients.
- UCSF developed the method now in use at many clinical research sites to isolate and transplant insulin-secreting pancreatic islet cells to treat type 1 diabetes. Active research also is underway at UCSF to prod stem cells into islet cells, and thereby provide an unlimited supply of the precious insulin-producing cells.
- Lewis Lanier, PhD, chair of the Department of Microbiology and Immunology, has discovered the genetic basis for the ability of certain kinds of immune cells, known as NK killer cells, to recognize and defend against viral infection and cancer. In ongoing research, Lanier’s team is investigating how these immune soldiers recognize and eliminate cells that have become transformed or infected by viruses. The new understanding offers major therapeutic promise.
Comprehensive Research in Infectious Diseases
A comprehensive infectious diseases research program at UCSF is aimed at understanding the transmission mechanisms of many microbial and parasitic pathogens, the nature and course of infections and the complications caused by multiple infections. The campus is particularly strong in molecular-level, genetic and pharmaceutical research needed to improve treatment of otherwise intractable infections, to boost disease resistance and to conquer microbial and parasitic pathogens worldwide.
One of the leading programs in the country, the Program in Microbial Pathogenesis and Host Defense is dedicated to gaining new insights into viral, bacterial, fungal and parasitic infections. The program functions as a research collective led by infectious diseases and immunology investigators, with studies covering both basic science and clinical research. Members of the research teams span all disciplines and departments.
Jay Levy, MD
Many projects study the interaction between microbes or parasites and their hosts during infection. Research projects include:
- Fungal infections: A number of laboratories at UCSF study fungi that cause disease. Fungal infections are a particular problem for individuals with compromised immune systems, including people with AIDS, transplant patients taking immunosuppressive drugs and patients on particular chemotherapy regimens. Microbial geneticist Anita Sil, PhD, MD, specializes in studying respiratory infections caused by fungi. Her lab focuses on Histoplasma capsulatum, a fungal pathogen that grows in soil and is thought to be the most common cause of fungal respiratory infections in healthy individuals. In addition to causing disease in a healthy host, H. capsulatum can be a major threat to patients with a disrupted immune response, including individuals taking particular medications for autoimmune disorders such as rheumatoid arthritis. Current studies in the Sil lab are investigating the identity and function of genes that allow the fungus to sense that it has moved from the soil to a host, and to shift its lifestyle accordingly. In addition, the lab studies how the fungus manipulates the human immune system to facilitate disease.
- Novel viruses: Charles Chiu, MD, PhD, heads the UCSF Viral Diagnostics and Discovery Center, which focuses on detection and discovery of novel viruses associated with acute illnesses (including respiratory infections, gastroenteritis and encephalitis), as well as chronic illnesses such as cancer. The center collaborates with other academic institutions, laboratories and hospitals. The center is actively using gene-tracking tools called microarrays to identify infectious microbes, so that appropriate therapies can be used to treat those who are infected. In 2003, this technology was successfully used to identify the severe acute respiratory syndrome virus, known as SARS, during a worldwide outbreak.
- Tuberculosis: Jeff Cox, PhD, a professor in the Department of Microbiology and Immunology, leads a prominent program studying the TB pathogen Mycobacterium tuberculosis, which is particularly adept at subverting host immune cell function. The research has identified a number of the bacterium’s genes necessary for infection, and carries out studies to learn how the microbe interacts with and changes its host’s defenses.
- Malaria and Chagas disease: A growing number of UCSF scientists are focusing on the search for new drugs against the world’s worst parasitic diseases, including malaria and Chagas disease, common in tropical America and a major cause of heart damage. Philip J. Rosenthal, MD, UCSF professor in the Division of Infectious Diseases, who is based at San Francisco General Hospital, is investigating the biochemistry of malaria parasites, and is conducting clinical and translational studies of antimalarial drug effectiveness and resistance in Africa. A team of parasitic disease experts, geneticists, biochemists and drug-screening experts has concentrated on the Chagas parasite, identifying a potential protein target, testing a new drug in animal models and now preparing for phase I clinical trials. The project, a collaboration among many levels of expertise that is rare at a single institution, is led by Jim McKerrow, MD, PhD, a professor in the Department of Pathology.
Nadia Roan, PhD, Warner C. Greene, MD, PhD
The University maintains an aggressive HIV research program geared to developing strategies to prevent, treat and cure HIV infection. A strong international effort focuses on behavioral and organizational responses to high infection rates, and promotes new clinical practices, drug treatment and vaccine research.
The AIDS Research Institute (ARI) is one of the premier AIDS research centers in the world. ARI coordinates and integrates all AIDS research activities at UCSF, supporting interdisciplinary collaboration aimed at all aspects of the epidemic in the United States and worldwide. The effort brings together hundreds of scientists internationally and more than 50 programs at UCSF and affiliated labs and institutions. Research ranges from fundamental studies of HIV at the molecular level to close clinical research collaborations with HIV-affected communities.
Highlights of UCSF HIV/AIDS basic science and clinical research include:
- Jay Levy, MD, who in 1983 isolated the human immunodeficiency virus (HIV), was also the first to report the presence of HIV in the brain and bowel, and to link it to diseases in these tissues. His research group also first demonstrated the ability of certain proteins (CD8+ Antiviral Factor, or CAF) to suppress HIV in a small number of healthy HIV-infected individuals. His lab maintains an aggressive effort to further define and synthesize this protective protein for potential treatment.
- Warner C. Greene, MD, PhD, UCSF professor of medicine and of microbiology and immunology, is director of the UCSF-affiliated Gladstone Institute of Virology and Immunology. Greene’s research focuses on the molecular basis of HIV transmission, disease progression and latency, and the biochemical mechanisms underlying the regulation of key genes. The lab also studies the mechanisms of transmission of HIV across the female genital mucosa.
- Researchers in the UCSF Division of Experimental Medicine, based at San Francisco General Hospital, investigate the human immunology of HIV and other chronic infections in patient-oriented research, bringing together basic scientists and clinician-scientists to speed the translation of research aimed to develop effective HIV treatments and vaccines. The HIV research by Mike McCune, MD, PhD, a professor in the division, has led to the definition of basic principles by which the human immune system develops and functions.
- Steven Deeks, MD, professor of medicine, is a recognized expert in clinical research to identify how HIV interacts with an infected patient’s immune system. He directs a research program investigating some of the possible effects of HIV-related inflammation on aging and other changes in infected patients.