CCHI Investigator Bios

JEFFREY V. RAVETCH, M.D., PH.D., CCHI Principal Investigator, Project 1 Leader
Theresa and Eugene M. Lang Professor
Leonard Wagner Laboratory of Molecular Genetics and Immunology

Dr. Ravetch dissects the cellular and molecular mechanisms that govern the generation of antibody specificity and the translation of that specificity into cellular responses. By identifying the genetic components that cause immune system cells to respond to specific antibodies, Dr. Ravetch hopes to gain a better understanding of how a functioning immune system protects organisms from invaders, and how a dysfunctional immune system attacks the body’s own tissues.

The Ravetch laboratory analyzes systemic autoimmunity in mouse models of certain diseases by investigating the genesis and fate of the pathological antigen-antibody complexes that form and trigger tissue damage. They simplify this complex problem by examining the mechanisms through which immune complexes influence both the afferent and efferent immune responses by interacting with a family of low-affinity surface receptors, the Fc receptors. These receptors are expressed as pairs of activation and inhibitory molecules, providing a mechanism for establishing thresholds for cellular triggering and for terminating the activation response. Disruptions of these pathways have revealed the central role these receptors play in appropriate immune responses.

Dr. Ravetch has shown that inhibitory Fc receptors for immunoglobulin G (IgG) are responsible for maintaining peripheral tolerance; animals without inhibitory Fc receptors develop spontaneous autoimmunity and autoimmune disease. Conversely, a deficiency of activation Fc receptors results in a protective effect, in which mice susceptible to autoimmune disease fail to develop it. But loss of activation receptors does not alter the development of autoantibody and immune complex deposition. Rather, Dr. Ravetch has found that these potentially pathogenic complexes are unable to trigger effector cell responses and are therefore benign. His lab is now investigating the precise cellular pathways engaged by activation receptors via autoantibodies by generating cell type-specific targeted gene disruptions of relevant activation receptors and by identifying the downstream effector molecules responsible. Recent work from the Ravetch lab showed that a sugar attached to IgG antibodies confers their protective ability; they are now working on a synthetic therapy rich in these sugar-linked antibodies.

Another focus in the Ravetch lab is the circuits involved in coordinating the regulation of activation and inhibitory receptors, in order to determine the signals that shift the balance from inhibition to activation. He has demonstrated that removing the inhibitory pathway in vivo, for example, can dramatically increase the potency of a cytotoxic antitumor antibody. This was the first demonstration of antibody-dependent cell cytotoxicity in vivo. Current studies are now aimed at manipulating the inhibitory response to enhance or limit the cytotoxicity of antibodies in vivo to better understand the role these pathways play in protective immunity and their therapeutic potential.

The lab is also working to determine the pathways through which the coupling of innate and adaptive mechanisms are coordinated to initiate an immune response. Two such pathways are currently under investigation: the feedback by immune complexes on antigen presentation and the targeting of selected antigens to restricted follicular locations to initiate T cell independent responses. Using a series of mice deficient in specific Fc receptors and immune complexes designed to selectively engage these pathways, they are determining the role of each in activating or tolerizing presenting cells in vivo.

Work by Dr. Ravetch led to the cloning and mapping of the first malarial parasite chromosome and more recently to the cloning of the first Fc receptor genes. He discovered how immunoglobulin receptors mediate antibody-triggered inflammation and determined the mechanism by which intravenous immunoglobulin causes immunosuppression. He also played a key role in establishing Fc receptor pathways as an essential part of the immune response and in describing the mechanisms of antibody-mediated effector responses.

Dr. Ravetch graduated from Yale University in 1973 and received his Ph.D. in 1978 from The Rockefeller University, where he studied under Norton Zinder and Peter Model. He received his M.D. from Cornell University Medical College in 1979 and completed his postdoctoral research at the National Institutes of Health with Philip Leder. In 1982 Dr. Ravetch joined the faculty of Memorial Sloan-Kettering Cancer Center and in 1984 also became a guest investigator in Rockefeller’s Laboratory of Cellular Physiology and Immunology. He was appointed professor at Rockefeller in 1996 and named Theresa and Eugene M. Lang Professor in 1997.

Dr. Ravetch received the Canada Gairdner International Award and the Sanofi-Pasteur Award in 2012, the Coley Award from the Cancer Research Institute in 2007, the American Association of Immunologists-Huang Foundation Meritorious Career Award in 2005, the Lee C. Howley Sr. Prize for Arthritis Research in 2004 and the Burroughs Wellcome Fund Award in Molecular Parasitology in 1986. He is a fellow of the American Academy of Arts and Sciences and the American Association for the Advancement of Science and a member of the National Academy of Sciences and the Institute of Medicine.

http://www.rockefeller.edu/research/faculty/labheads/JeffreyRavetch/

MICHEL C. NUSSENZWEIG, M.D., PH.D., Project 2 Leader
Investigator, Howard Hughes Medical Institute
Senior Physician
Zanvil A. Cohn and Ralph M. Steinman Professor
Laboratory of Molecular Immunology

Unlike many organ systems present throughout evolution, the immune system occurs only in vertebrates. Although this places a limit on classical genetic analysis, Dr. Nussenzweig’s laboratory circumvents the problem by combining biochemistry and molecular biology with gene targeting and transgenic technologies to better understand the molecular aspects of adaptive and innate immune responses. He focuses on B lymphocytes and antibodies for adaptive immunity and on dendritic cells in his studies of innate immunity.

The function of the immune system is to protect vertebrates from a multitude of different pathogens, and there are two types of immune responses that have evolved to accomplish this task: innate and adaptive immunity. Lymphocytes are the primary effectors of adaptive immunity and assemble a diverse repertoire of immune receptors using a somatic gene recombination process known as V(D)J recombination. This process enables the production of a very large number of unique receptors that are able to recognize almost any antigen, but it also produces self-reactive receptors, which must be silenced to prevent autoimmune diseases.

A series of checkpoints has evolved to ensure that B cells emerging from the bone marrow carry functional and non-self-reactive antigen receptors. Dr. Nussenzweig’s laboratory has examined the regulation of these checkpoints and found that many depend on signals from membrane immunoglobulin. In its absence, B cells fail to pass the checkpoints and die by apoptosis. Ongoing research focuses on understanding checkpoint regulation, the mechanisms that veto autoimmune antibody production and how this breaks down in autoimmune diseases.

Although V(D)J recombination produces a multitude of antigen receptors, they are relatively low-affinity receptors that must be refined by somatic hypermutation and class switch recombination to produce the high-affinity antibodies that protect against most pathogens. The lab is investigating the molecular basis of these diversification reactions and how they can occasionally lead to cancer-associated chromosome translocations.

A second area of interest for the Nussenzweig lab is the physiological function of dendritic cells. To examine the function of dendritic cells in the steady state, he and his colleagues devised an in vivo antigen delivery system that uses a monoclonal antibody and a dendritic cell-restricted endocytic receptor, DEC-205. This route of antigen delivery is several orders of magnitude more efficient in inducing T cell activation and cell division than free peptide in strong adjuvants. But the activation response is not sustained, and T cells become unresponsive to systemic rechallenge with antigen. Coinjection with anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity, indicating that in the steady state, the primary function of dendritic cells is to maintain peripheral tolerance.

Dr. Nussenzweig’s experiments are consistent with the notion that self-antigens induce tolerance. In contrast, antigens taken up by dendritic cells in the context of activation stimuli, such as those found during inflammation or tissue destruction, induce prolonged T cell activation. This steady-state tolerizing function of dendritic cells may be essential to their role in eliciting immunity. During inflammation or infection, they present self-antigens simultaneously with non-self. By establishing tolerance to self before challenge with pathogens, dendritic cells can focus the adaptive immune system entirely on the pathogen, thereby avoiding autoimmunity. The ability to target antigens to dendritic cells and control their function in vivo has significat implications for the development of vaccines and therapies for autoimmunity. Recently, the lab defined distinct progenitor lineages for classical spleen dendritic cells, plasmacytoid dendritic cells and monocytes, a useful step toward antigen-specific targeting.

Dr. Nussenzweig received his bachelor’s degree from New York University in 1975. He received his Ph.D. in 1981 from The Rockefeller University, where he studied under Ralph M. Steinman, and his M.D. in 1982 from the New York University School of Medicine. He continued his clinical training at Massachusetts General Hospital, first as an intern and resident in internal medicine from 1982 to 1985 and then as a clinical fellow in infectious diseases from 1984 to 1985. In 1986 he began his postdoctoral research in genetics at Harvard Medical School and returned to Rockefeller in 1990 as assistant professor. He was named associate professor in 1994 and professor and senior physician in 1996. He has been an investigator at the Howard Hughes Medical Institute since 1999.

Dr. Nussenzweig was elected to the U.S. National Academy of Sciences and the Brazilian Academy of Sciences in 2011 and the Institute of Medicine in 2009. He received the Lee C. Howley Sr. Prize for Arthritis Research in 2008, the American Association of Immunologists-Huang Foundation Meritorious Career Award in 2004 and the Solomon A. Berson Alumni Achievement Award for Basic Science from New York University in 2003. He is a member of the American Academy of Arts and Sciences.

http://www.rockefeller.edu/research/faculty/labheads/MichelNussenzweig/

CHARLES M. RICE, PH.D., Project 4 Leader
Maurice R. and Corinne P. Greenberg Professor in Virology
Laboratory of Virology and Infectious Disease

Globally, an estimated 130 million people are infected with hepatitis C virus (HCV), a major cause of acute hepatitis and chronic liver disease, including cirrhosis and liver cancer. There is currently no HCV vaccine, and although new antiviral drugs were recently approved and are clinically available, more will be needed to combat resistance and target all genotypes. Dr. Rice’s lab focuses on understanding virus replication, host responses to infection and developing new therapies to treat HCV and other viral pathogens.

The Rice lab seeks new ways of blocking HCV infection by studying how the virus replicates. Traditionally, blocking the actions of essential viral enzymes has been key to generating effective antiviral drugs. With collaborators at the University of Missouri, the lab has been studying drug combinations and the mechanisms of drug resistance. Dr. Rice’s group has also analyzed the biochemistry and structure of a number of HCV proteins, such as the viral helicase, the nonstructural protein NS5A, and the NS2-3 autoprotease. Since all are necessary for virus replication, understanding how they work may help in the design of new inhibitors that target these proteins.

Another of Dr. Rice’s research interests is the development and improvement of systems to propagate viruses in vitro and in vivo. For example, growing HCV in cell culture has been difficult and restricted to only a few select genotypes and isolates. Recently, the Rice group found that overexpressing selected host cell proteins allows growth of a broader number of HCV isolates, and studies of the mechanism by which these proteins promote replication are underway. A collaborative effort with colleagues at the Massachusetts Institute of Technology has resulted in improved methods to infect otherwise healthy human hepatocytes in culture. Unlike previous culture models, which depend on cancerous cells, HCV infection of normal liver cells may more accurately reflect what happens in a patient and yield clues about how the virus causes disease. More recently, this work has been extended to studies of the viral life cycle in stem cell-derived hepatocytes, which is paving the way toward personalized medicine applications. Alongside improving culture systems, Dr. Rice’s group has pioneered new methods to concentrate HCV, enabling analysis of its structure and composition with electron microscopy, which in turn, will inform the design of vaccines and new drugs targeting virus particles. Additionally, the Rice lab has been developing an HCV-permissive transgenic mouse model, and also animals engrafted with human liver and immune tissues susceptible to HCV infection and capable of mounting human virus-specific immune responses.

The Rice lab is also interested in developing bioinformatic approaches to study host-virus interactions at a systems level. Using novel techniques such as HITS-CLIP and RNAseq, the Rice lab is analyzing the role of cellular micro RNAs and RNA-binding proteins in regulating the replication of HCV and other RNA viruses. Laser-capture microdissection of infected, uninfected, and bystander cells has allowed specific comparisons of the cellular responses at a genetic level. Because these experiments can be applied in a variety of settings, such as different viruses, chronic vs. acute infection, different genotypes or cell types, they will help to illuminate the complex relationship between host and pathogen in a panoramic and genome-wide view.

The strategies that viruses use to escape from host defenses are of significant interest, as failure of the immune response can result in chronic disease. Even as viruses evade adaptive immunity, innate antiviral mechanisms may limit their replication and spread. Exploiting innate cellular factors that limit viral entry and replication is an additional strategy for developing antiviral therapeutics. The Rice lab recently reported a comprehensive screen for antiviral activities of naturally occurring cellular defense proteins, termed interferon-stimulated genes (ISGs). Interestingly, unique combinations of these genes, or “ISG profiles,” were found to target different viruses. Understanding the mechanisms of ISG inhibition is a prerequisite to potential exploitation of these processes to interfere with virus growth, and mechanistic studies are underway. The zinc-finger antiviral protein (ZAP) is an ISG that potently inhibits the replication of members of the Alphavirus genus. Using the prototype alphavirus, Sindbis virus, as a model system, investigators led by Research Associate Professor Margaret R. MacDonald are working to understand ZAP’s mechanism and how it functions in concert with other ISGs. Dr. MacDonald is also investigating the role of cellular chaperone proteins in flavivirus RNA replication.

Together, all these investigations interrogate both sides of the virus-host cell relationship, with the overarching objective of designing efficacious new therapies and vaccines. Additional studies underway on viral pathogens related to HCV, such as dengue virus, yellow fever virus, and influenza A virus will shed light on the specificities of their interactions with host cells. They will also be broadly instructive toward novel strategies to tip the balance in the age-old warfare between pathogenic viruses and their hosts.

Dr. Rice received his Ph.D. in biochemistry in 1981 from the California Institute of Technology, where he was then a postdoctoral research fellow from 1981 to 1985. Before he joined Rockefeller in 2000, he spent 14 years on the faculty of the Washington University School of Medicine. Dr. Rice is scientific and executive director of the Center for the Study of Hepatitis C, an interdisciplinary center established jointly by The Rockefeller University, NewYork-Presbyterian Hospital and Weill Cornell Medical College. Dr. Rice is a member of the National Academy of Sciences.

http://www.rockefeller.edu/research/faculty/labheads/CharlesRice/

BRAD ROSENBERG, M.D., Ph.D., Project 4 Co-Investigator
John C. Whitehead Presidential Fellow

Recent advances in DNA sequencing technologies and computational analysis have made it possible to explore massive sets of biological information in unprecedented detail. Dr. Rosenberg’s lab aims to apply these technologies to the study of antigen receptor diversity in the adaptive immune system. Using a combination of molecular biology, microfluidics and high throughput DNA sequencing, the lab is developing a method for profiling T and B cell antigen receptors in large, complex populations of cells. This approach will be used to study the antigen receptor repertoire as it relates to immune function in contexts such as infection, vaccination and autoimmune disease. Aside from immunology, these research tools are expected to have broad utility for many other biological systems in which genes of interest contain different sequences distributed within a complex cell mixture. Additional research efforts in the laboratory include identifying noncanonical mRNA modifications and characterizing the innate immune response to viral infections.

http://www.rockefeller.edu/research/faculty/independentfellows/BradRosenberg/

SARAH J. SCHLESINGER, M.D., Service Core, Pilot Core Leader
Senior Attending Physician and Associate Professor of Clinical Investigation
Laboratory of Molecular Immunology

Dr. Schlesinger leads the clinical development of vaccines that target HIV and immunotherapies to treat other conditions, including cancer. Formally a member of the Steinman laboratory and now working with Michel Nussenzweig and Jeffrey Ravetch, she is interested in the clinical manipulation of the immune system’s dendritic cells to elicit immunity to diseases ranging from HIV to cancer. Although much research has been conducted in mice, the causes of human disease can differ considerably. Dr. Schlesinger is directing phase I clinical studies that employ the methods of immunology and dendritic cell biology, in which patients set the standards needed to understand diseases and treatments.

Dr. Schlesinger has been involved in the clinical trials of eight HIV vaccines and vaccine adjuvants. She is now conducting the first HIV vaccine trial based on dendritic cells, which were discovered at Rockefeller in 1973 by Ralph Steinman and his mentor, Zanvil Cohn.

In the steady state, dendritic cells capture antigens and travel to immune or lymphoid tissues, where they present to T cells, stimulating a robust immune response. But dendritic cells also play a seemingly opposite role, immune tolerance, which silences dangerous immune cells and prevents them from attacking the body’s own tissues. Working with Dr. Steinman, Dr. Schlesinger has used dendritic cells to study and design treatments that can harness the immune system, either to enhance or silence its functions, in an antigen- or disease-specific manner.

In addition to leading clinical trials, Dr. Schlesinger chairs the research education and training committee of the Center for Clinical and Translational Science at The Rockefeller University Hospital. She is also codirector of the Clinical Scholars program and the Certificate in Clinical and Translational Sciences program and is a member of The Rockefeller University Institutional Review Board.

http://www.rockefeller.edu/research/faculty/researchaffiliates/SarahJSchlesinger