Main content

    Kalmanovitz Liver Immunology Laboratory at
    California Pacific Medical Center

    California Pacific Medical Center's Liver Immunology Laboratory serves as a hub for collaborative viral hepatitis research in the San Francisco Bay Area. Founded in 2006 under the direction of Stewart Cooper M.D., the lab's focus is translational research studies that make major clinical problems the driving force for scientific discoveries aimed at improving disease care. Our Liver Biorepository assists in our translational research efforts by providing clinically annotated human samples from individuals with liver disease.

    Overview

    Our laboratory combines research in immunology and hepatology by studying infection with hepatitis C virus (HCV) and more recently hepatitis B virus (HBV), major global causes of advanced liver disease and liver cancer. Ultimately, the goals of our studies are four-fold:

    1. developing a HCV vaccine;

    2. developing better HCV therapies aimed at improving treatment outcome and slowing liver disease progression;

    3. improving liver transplant outcomes for patients with hepatitis C; and,

    4. understanding the mechanism of hepatitis B activation
    Our research is driven by major trends and problems observed in clinical liver practice. For instance, we are studying immunological influences (genetic and cellular) on disease outcomes in patients with hepatitis C, including those who undergo liver transplantation. Hepatitis C causes progressive liver disease in approximately 30% of infected people and results in more liver transplants than any other cause. After transplantation, 20-25% of HCV-infected recipients will develop severe liver fibrosis (“scarring”) and potential transplant loss within five years. We suspect that progressive liver disease in both settings is largely mediated by immune responses, and is not due to the virus itself.


    Research

    A major thrust of our work is studying people with recently acquired HCV infection; a rarely studied period called “acute hepatitis C.” This is the period when the outcome of infection is naturally determined. An unusual feature of acute hepatitis C is that only a minority of people clears the virus. By studying early infection, we are able to compare immune responses in people who either clear HCV infection or develop progressive liver disease. We want to understand how such gifted people’s immune systems clear HCV. Our research involves the following:

    • Cellular Immunology
      People protect themselves from viral infections by deploying specialized cells, called lymphocytes, which engage and destroy most viruses that pose a threat. Our studies focus on engagement of HCV by different types of lymphocyte. These include natural killer (NK) cells, T cells and ‘hybrid’ lymphocytes called natural killer T (NKT) cells. NK and NKT cells are curiously plentiful in the liver. These lymphocytes can each kill virus-infected cells, secrete disinfecting chemicals and release molecular messages that strengthen or dampen the immune response.

    • Genetics
      Our scientists are studying approximately 40 related sets of genes that influence immune responses against hepatitis C and hepatitis B viruses. These include “killer cell immunoglobulin-like receptor” genes or KIR, and human leukocyte antigen (HLA) class I genes. Each of these genes has many versions. At the cell surface of NK and NKT cells, the proteins encoded by KIR genes can either activate or dampen an immune response by engaging the proteins made by HLA class I genes. The combination and type of KIR and HLA genes varies from person to person and may influence: a) why some people spontaneously clear HCV; b) why some people develop progressive liver damage.

    • Liver Transplantation
      A deeper understanding of the range of antiviral immune responses and how they are regulated may be key to improving post-transplant outcomes for hepatitis C. In the US and many other countries, hepatitis C is the leading indication for liver transplantation. Currently, approximately 20-25% of liver-transplant recipients with hepatitis C will develop severe liver disease within 3-5 years, resulting in graft loss. The reason for this remains a mystery. We suspect that the accelerated liver damage is mainly immune-mediated, and we are therefore examining immune responses in this setting. We consider this research essential for developing better treatment strategies and improving liver transplant outcome for patients with hepatitis C.

    • National & International Studies
      In addition to studying hepatitis C in the United States, we are collaborating with leading researchers in Europe, Asia and Egypt. Notably, Egypt has the world’s highest national prevalence of HCV infection where it is the second leading cause of death. Ninety-five percent of Egyptian HCV infections are caused by genotype 4 viruses, which are uncommon in the West.

    Resources

    We have a dedicated team of eight scientists. Due to the translational and leading-edge nature of our liver research, we attract applicants from universities around the world, including the Fulbright organization.

    The laboratory occupies approximately 2,000-square feet on California Pacific's Pacific Heights campus and is equipped with an expanding complement of modern instrumentation, novel reagents and experimental tools. We continually review our inventory and needs. We have instruments that amplify, image and analyze genes of interest, facilitate lymphocyte isolation and demonstrate lymphocyte activation in different ways. Our large equipment includes:

    • ‘CTL’ EliSpot Reader: It demonstrates release of specific chemicals by single cells, and is used to identify and quantify individual virus-specific lymphocytes among thousands of other cells extracted from a person’s blood or liver.

    • ‘Wallac’ Micro Beta Counter: This is a gamma radiation counter, which is used to demonstrate killing of virus infected cells by T and NK cells, and also to demonstrate virus-driven expansion of CD4+ T cells.

    • “FACSAria” Flow Cytometer and Cell Sorter: This high performance instrument allows identification of individual cells of interest among millions of other cells in human tissues. It is capable of simultaneously identifying up to 15 different molecules on any given cell, and of separating such individual cells from other cells to conduct further genetic and functional analyses.

    • Cesium Source: A high-energy gamma radiation source is now required to facilitate stimulation, expansion and study of lymphocytes from blood and liver of HCV and HBV infected patients.

    Funding

    The Liver Immunology Laboratory is funded by the National Institutes of Health (NIH) and by private donation. Philanthropy allows the laboratory to thrive and has helped ensure we have the breadth of equipment and staff necessary to pursue our research.

    Contacts

    Liver Immunology Laboratory
    California Pacific Medical Center
    2200 Webster Street, Gerbode Bldg. #209
    San Francisco, CA 94115
    Tel: 415-600-1548