Medical,Scientific Advisors
Medical, Scientific Advisors
Robert C. Gallo, MD
- Director of Institute of Human Virology (IHV)
- University of Maryland School of Medicine
Prior to the AIDS epidemic, Dr. Gallo was the first to identify a human retrovirus and the only known human leukemia virus - HTLV - one of few known viruses shown to cause a human cancer. In 1976, he and his colleagues discovered Interleukin-2, a growth regulating substance now used as therapy in some cancers and sometimes AIDS. And in 1986, he and his group discovered the first new human herpes virus in more than 25 years (HHV-6), which was later shown to cause an infantile disease known as Roseola and currently is hypothesized as a strong suspect in the origin of multiple sclerosis.
Prior to becoming director of the Institute of Human Virology in 1996, Dr. Gallo spent 30 years at the National Institutes of Health's National Cancer Institute, where he was head of its Laboratory of Tumor Cell Biology. A Connecticut native, his interest in science and medicine was first stirred by the loss of his 6-year-old sister to leukemia when he was just 12 years old. The physicians who cared for her made a lasting impression and Gallo would later make scientific research - and the opportunity to help put an end to deadly diseases - his life's work.
Dr. Gallo's research has brought him international recognition as well as election into the National Academy of Sciences and the Institute of Medicine. He has been awarded honors for his contribution to science from countries around the world and holds 29 honorary doctorates. Dr. Gallo was the most referenced scientist in the world in the 1980s and 1990s, during which he had the unique distinction of twice winning America's most prestigious scientific award - the Albert Lasker Award in Medicine - in 1982 and again in 1986. Dr. Gallo is the author of more than 1,200 scientific publications and the book "Virus Hunting - AIDS, Cancer & the Human Retrovirus: A Story of Scientific Discovery."
Bana Jabri, M.D./PhD.
My laboratory investigates the mechanisms underlying the development of complex inflammatory disorders. We combine human ex vivo studies, in vitro human model systems, and mouse models to determine the role of tissue and microbial signals in the regulation of tissue resident effector T cell responses. In human, we focus on the study of celiac disease, inflammatory bowel disease and type-1 diabetes. In early studies we identified a regulatory loop whereby stressed or infected tissue epithelial cells arm cytolytic T cells to kill them through the interplay of the cytokine IL-15, activating receptors of the natural killer (NK) family, and the stress-induced MHC-like ligands MIC and HLA-E. This innate tissue-mediated control of effector CTL constitutes a new layer of immune regulation with implications for disease mechanisms and treatments. We further characterized the innate signaling pathway regulating NK receptor and IL-15-mediated regulation of effector cytolytic T cells. These discoveries have led to the initiation of clinical trials aimed at targeting IL-15 in refractory celiac disease. In parallel, we characterized the role played by tissues and bacteria in the regulation of T helper cell responses. In particular, we demonstrated that retinoic acid acquired adjuvant properties under conditions of sterile inflammation associated with IL-15 overexpression in the lamina propria. More recently, my laboratory is developing new lines of investigations aimed at addressing the role of host-viral interactions in the loss of tolerance to dietary antigens and the role of epigenetic in the shaping of T cell responses by the tissue environment in which they reside.
Steve Jacobson PhD., collaborator
- Chief of Viral Immunology Section
- Neuroimmunology Branch, NINDS
- National Institutes of Neurological Diseases and Stroke
- National Institutes of Health
Human T lymphotropic virus type I (HTLV-I) is associated with a chronic progressive neurological disorder known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease clinically similar to the chronic progressive form of multiple sclerosis (MS). Other viruses such as human herpes virus type 6 (HHV-6) have been associated with MS. An understanding of the pathogenesis of a neurologic disease with a known viral etiology will aid in defining similar mechanisms of pathogenesis in MS, a disease of unknown etiology.
Areas of research addressing these neurovirological and neuroimmunological issues include: the host immune response in HAM/TSP, particularly the role of CD8+, HTLV-I-Tax protein-specific cytotoxic T lymphocytes (CTL), and the detection of these immunopathogenic CTL as well as the localization of human retroviral sequences in the central nervous system of HAM/TSP patients. Furthermore, his group is interested in studying the association of HHV-6 and MS and development of immunotherapeutic strategies for the treatment of HAM/TSP, including a clinical trial of IFN-beta therapy.
Major findings include: The demonstration of spontaneous proliferation of CD4+ and CD8+ cells from HAM/TSP patients ex vivo, including Tax-specific CD8+ CTL directly isolated from PBL of HAM/TSP patients, the quantitation of HTLV-I DNA in PBL of HAM/TSP patients by real-time Taqman PCR, identification of altered peptide ligands that have been shown to interfere specifically with antigen-specific CTL clones, association of HHV-6 and MS based on increased IgM response to HHV-6 early antigen, detection of HHV-6 DNA in sera from MS patients, and the observation of an increased proliferative response to the HHV-6A variant in MS patients. Collectively, these results continue to define the role of human viruses in chronic progressive neurologic disease.
Dr. Jacobson has won numerous awards for his role in his studies of neurological diseases associated with virus infections. He has over 100 publications and has been a frequent speaker in international conferences. He has been considered one of the leading experts in HAM/TSP studies and has run several clinical trials for the disease at the NIH.
Wuyuan Lu, PhD
- Professor of Department of Biochemistry and Molecular Biology
- Institute of Human Virology (IHV)
- School of Medicine University of Maryland
Dr. Lu’s interest ranges from his ground breaking studies in protein engineering via total chemical protein synthesis to discovery of novel peptides for targeted therapy. Currently he is interested in knowing what happens to functional properties of proteins when their side chains and backbone structures are altered in a way that is genetically unattainable. His group functionally and structurally characterizes proteins that are chemically assembled from (coded and non-coded) individual amino acids.
Another area of Dr. Lu’s interest is studying a class of anti-microbial peptides that are expressed in leukocytes and epithelial cells. They are broadly active against bacteria, fungi, and viruses, playing important roles in innate host defense against microbial infection. His studies are aimed at deciphering the molecular determinants of diverse functions of human defensins and elucidating their mechanisms of action in a variety of biological processes. Such knowledge may help design new anti-infective peptides to fight off infectious diseases.
One of Dr. Lu’s main focuses has been in discovery of novel antiviral and antitumor peptides for targeted molecular therapy. Compared with small molecule inhibitors, peptides are capable of antagonizing target proteins with high affinity and unsurpassed specificity. This line of research centers on applying the contemporary tools of synthetic protein chemistry, phage display, structural biology, and drug delivery to the discovery of peptide antagonists with desirable pharmacokinetic properties and functionalities that may be explored for therapeutic use. His targets include but not limited to HIV-1 matrix and capsid proteins as well as oncogenic proteins that negatively regulate the tumor suppressor protein p53.
Dr. Lu is the author or more than 80 peer-reviewed publications and has been the recipient of several NIH grants and scientific awards for his work in peptide and protein chemistry.
Tom Waldmann, M.D.
Thomas A. Waldmann, M.D. received his M.D. from Harvard Medical School. He joined the NCI in 1956, and has been Chief of Metabolism Branch since 1973. Over his 59-year career he defined the IL-2 receptor subunits, IL-2R beta and IL-2R alpha using the first-ever reported anti-cytokine receptor monoclonal antibody (anti-Tac, daclizumab, Zenapax). These studies culminated in the definition of the IL-2 receptor as an exceptionally valuable target for monoclonal antibody mediated therapy of leukemia, lymphoma, and multiple sclerosis. He co-discovered IL-15, elucidated its role in persistence of NK and CD8 memory T- cells and completed the first in-human trial of IL-15 in patients with metastatic malignancy. He introduced blockade of the IL-15/IL-15 receptor and its Jak/STAT signaling pathway for leukemias and autoimmune diseases where gamma-c cytokines including IL-15 play a pathogenic role. His honors include: the Ehrlich Medal, Abbott Laboratories Prize, Bristol-Myers Squibb Award for Distinguished Achievement in Cancer Research, Milken Family Medical Foundation Distinguished Basic Scientist Award, Artois-Baillet Latour Health Prize, AAI-Dana Foundation Award in Human Immunology Research and election to the National Academy of Sciences, The SAMMIE Life Time Achievement Award, identification as an NIH Distinguished Investigator, American Academy of Arts and Sciences, Institute of Medicine of the National Academy of Sciences and Royal Society of the Medical Sciences (UK).
For five decades, Thomas Waldmann has been a brilliant scientist internationally recognized for his research, which extends from fundamental molecular and cellular immunology to innovative clinical trials of cancer immunotherapies using monoclonal antibodies and cytokines. His seminal cancer research has led to cutting-edge discoveries, including the characterization of new cytokines, receptors and regulatory pathways, and disorders of these elements that underlie T-cell leukemogenesis. Waldmann translated his basic insights into novel cytokine receptor-directed treatments for T-cell leukemia/lymphoma and autoimmune disorders. His discoveries concerning cytokines and their receptors, as well as his development of monoclonal antibody- mediated therapy directed toward these elements, have great implications for cancer therapy and other medical arenas.
Waldmann’s pivotal studies revolutionized our understanding of the roles played by the IL-2/IL-2 receptor and IL-15/IL-15 receptor cytokine systems in the life and death of T-lymphocytes in normal and leukemic states. He defined the IL-2 receptor subunits IL- 2R-beta and IL-2R-alpha using the first-ever reported anti-cytokine receptor monoclonal antibody (anti-Tac, daclizumab), which he developed (J. Immunol 126:1393, 1981, Nature 311:626, 1984). His seminal work with the IL-2 receptor revealed that its subunits are exceptionally valuable targets for therapy of leukemia and autoimmune diseases (Blood 82:1701, 1993). The scientific basis for this approach was his demonstration that virtually no normal cells express IL-2R-alpha, whereas it is expressed by abnormal T-cells in lymphoid malignancies, autoimmune disorders, and T-cells involved in allograft rejection. Waldmann introduced different forms of IL-2 receptor- directed therapy, including unmodified antibodies to IL-2R-alpha (anti-Tac, the first antibody a cytokine receptor to receive FDA approval), humanized anti-Tac (daclizumab, Zenapax), and daclizumab armed with toxins or alpha and beta-emitting radionuclides. Daclizumab contributed to the reducing renal transplant rejection, leading to its approval by the FDA (Transplantation 51:107, 1991). In addition, Dr. Waldmann found it useful against T-cell mediated autoimmune diseases, including noninfectious uveitis (Proc. Natl. Acad. Sci. USA 96:7462, 1999). Furthermore, with such therapy he achieved a 78% reduction in gadolinium-enhanced MRI lesions in patients with multiple sclerosis (Proc. Natl. Acad. Sci. USA 101:8705, 2004). In validation of this result, Daclizumab therapy significantly reduced the number of new or enlarged lesions compared to a placebo in an over 200 patient randomized double-blind, placebo-controlled trial in patients with relapsing multiple sclerosis being treated with interferon beta. Waldmann further demonstrated that anti-Tac provides effective therapy for select patients with T-cell lymphoid malignancies, including HTLV-I-associated adult T-cell leukemia.
In other translational efforts, Waldmann extended his pioneering use of monoclonal antibodies as cancer therapy. Using a model of human T-cell leukemia/lymphoma in immunodeficient mice he developed, Waldmann demonstrated effective therapy with monoclonal antibodies directed toward the T-cell antigens CD2, CD25, CD30 and CD52. He therefore tested these monoclonal antibodies in patients with T-cell malignancies and achieved remissions with each agent. Waldmann also augmented the effectiveness of monoclonal antibodies by arming them with toxins and radionuclides. In a clinical trial involving patients with HTLV-I associated adult T-cell leukemia, Waldmann showed that anti-Tac armed with 90Y yielded remissions in over 50% of trial patients (Blood 86:4063, 1995). Waldmann’s insights and discoveries have made him a world leader in the rational development and use of monoclonal antibodies.
Waldmann is co-discoverer of the cytokine, IL-15 and elucidated its role in the development and persistence of NK cells and CD8 memory cells (Proc. Natl. Acad. Sci. USA 91:4940, 1994, Nature Review Immunol. 6:595, 2006). He demonstrated that IL-15 binds to a cytokine-specific IL-15R-alpha chain as well as beta and gamma chains that are shared with the IL-2 receptor system. Despite this sharing of receptor components, he showed that IL-2 and IL-15 make distinct contributions to adaptive immune responses (Immunity 14:105, 2001). IL-2, through its induction of regulatory T-cells and activation-induced cell death (AICD), is involved in the T-cell suicide required for self tolerance. In contrast, IL-15 inhibits AICD and favors the survival of CD8 memory cells and is thus dedicated to supporting persistence of an immune response to invading pathogens. In a landmark observation, Dr. Waldmann showed that IL-15 acts as a cell- membrane-associated molecule as part of an immunological synapse (Immunity 17:537, 2002). IL-15 and its private receptor, IL-15R alpha are induced onto the surface of antigen-presenting cells, including dendritic cells. IL-15R-alpha presents IL-15 in trans to neighboring NK and memory and effector T cells. Waldmann therefore tried replacing IL-2 with IL-15 in the treatment of renal cell malignancy and malignant melanoma in animals, and he found it effective. He is now developing IL-15 for clinical trials (Blood 105:721, 2005). Furthermore, Waldmann demonstrated that vaccinia vaccines containing IL-15 induced long-lasting CD8 mediated CTL immunity whereas T-cell immunity mediated by IL-2 was short-lived (Proc. Natl. Acad. Sci. USA 100:3392, 2003). Thus, Waldmann’s proposals for using IL-15 as a cytokine and its incorporating it into molecular vaccines may represent major advances in the therapy of cancer and AIDS and in vaccine design. In parallel studies, Waldmann identified IL-15 over-expression in patients with autoimmunity and leukemia including disorders associated with HTLV-I (Proc. Natl. Acad. USA 98:14559, 2001). He reported that the monoclonal antibody humanized Mik-Beta-1 directed toward IL-2/IL-15R beta, a receptor he co-discovered, prevents the transpresentation of IL-15 to NK and CD8 T-cells thereby inhibiting IL-15 actions (Proc. Natl. Acad. Sci. USA 83:9694, 1986, 91:4940, 1994). Waldmann is translating these IL-15-blockade observations into clinical trials using humanized Mik-Beta-1 in patients with autoimmunity or CD8 T-cell lymphoma.
Collectively, Waldmann’s scientific odyssey has shown great originality and scientific novelty. They have contributed to research accelerating progress against cancer and have major implications for future discoveries. His studies have dominated the field of cytokines and their control of the T-cell immune response and have defined the molecular disorders underlying autoimmune diseases and T-cell leukemogenesis. Waldmann’s fundamental research and medical insights have allowed him to translate his laboratory findings into new therapies. Thus, Dr. Waldmann is a pioneer and leader in producing the explosion of knowledge about cytokines and their receptors and in the coming age of monoclonal antibodies, now a dominant form of immunotherapy with 400 such agents currently in clinical trials.