Interleukins are cytokine molecules responsible for regulating the activities of the cells that mediate immune/inflammatory reactions. The Smith laboratory is focused on the interleukin-2 (IL-2) molecule, which is the first cytokine molecule to be identified, characterized and purified to homogeneity [1]. IL-2 is a 15.5 kDa globular glycoprotein secreted by antigen-activated T lymphocytes (T cells) that binds to high affinity IL-2 receptors on antigen-activated T cells [2], and thereby promotes their survival, proliferative clonal expansion and differentiation to effector T cells [3, 4]. The IL-2-stimulated clonal expansion of antigen-selected T cell and B cell clones determines the tempo and magnitude of antigen-specific immune responses, and forms the basis for immunological memory [4, 5]. IL-2 mediates its effects by activating the expression of specific genes [6]. Accordingly, methods have been developed to identify and clone IL-2-regulated genes [7], and more recently via the use of DNA microarrays [8]. In addition to promoting immune responses, IL-2 is crucial for the development of self-nonself recognition, an aspect of the immune system that allows for reaction to all foreign environmental antigens, thereby providing protection from potentially harmful molecules and organisms, but prevents autoimmunity [9]. The understanding of the IL-2/IL-2R interaction at the molecular level [10] has led Smith to propose the Quantal Theory of Immunity [11, 12], which explains how a definite number of IL-2/IL-2R interactions are counted by each cell, and that a cell reacts in a quantal (all-or-none) fashion only if a definite number of interactions has occurred. This understanding of how the immune system functions at the molecular level has provided the impetus for Smith and his team to explore ways to use IL-2 therapeutically, in particular as an adjuvant for vaccines [13].
1.Smith KA, Favata MF, Oroszlan S: Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics. J Immunol 1983, 131:1808-1815.
2.Robb RJ, Munck A, Smith KA: T cell growth factor receptors: Quantitation, specificity, and biological relevance. J Exp Med 1981, 154:1455-1474.
3.Cantrell DA, Smith KA: The interleukin-2 T-cell system: a new cell growth model. Science 1984, 224:1312-1316.
4.Smith KA: Interleukin-2: inception, impact, and implications. Science 1988, 240:1169-1176.
5.Ehlers S, Smith KA: Differentiation of T cell lymphokine gene expression: the in vitro acquisition of T cell memory. J Exp Med 1991, 173:25-36.
6.Stern JB, Smith KA: Interleukin-2 induction of T-cell G1 progression and c-myb expression. Science 1986, 233:203-206.
7.Beadling C, Johnson KW, Smith KA: Isolation of interleukin 2-induced immediate-early genes. Proc Natl Acad Sci U S A 1993, 90:2719-2723.
8.Beadling C, Smith K: DNA array analysis of interleukin-2-regulated immediate/early genes. Med Immunol 2002, 1: 2
9.Klebb G, Autenrieth IB, Haber H, Gillert E, Sadlack B, Smith KA, Horak I: Interleukin-2 Is Indispensa ble for Development of Immunological Self-Tolerance. Clinical Immunology and Immunopathology 1996, 81:282-286.
10.Smith K: The structure of IL2 bound to the three chains of the IL2 receptor and how signaling occurs. Med Immunol 2006, 5:3.
11.Smith K: The quantal theory of how the immune system discriminates between "self and non-self". Med Immunol 2004, 3:3.
12.Smith K: The quantal theory of immunity. Cell Res 2006, 16:11-19.
13.Smith K, Andjelic S, Popmihajlov Z, Kelly-Rossini L, Sass A, Lesser M, Benkert S, Waters C, Ruitenberg J, Bellman P: Immunotherapy with Canarypox Vaccine and Interleukin-2 for HIV-1 Infection: Termination of a Randomized Trial. PLoS Clin Trials 2007, 2 3.
For additional information, see:
http://www.cornellmedicine.com/ser_div/imm_res.html?name1=Immunologytype1=2Select http://www.cornellmedicine.com/ser_div/imm_edu.html?name1=Immunologytype1=2Select http://www.med.cornell.edu/research/kasmith/
Kendall A. Smith is the Rochelle Belfer Professor of Immunology and Medicine at Cornell University's Weill Medical College and Graduate School of Biomedical Sciences. He is also a Senior Attending Physician and Chief of The Division of Immunology at The New York Presbyterian Medical Center.
Smith graduated with a B.S. in biology from Denison University, Granville, Ohio and received his M.D. summa cum laude from The Ohio State University College of Medicine. After clinical training in Medicine at Yale-New Haven Hospital, and hematology/oncology research at the National Cancer Institute and Dartmouth Medical School, Dr. Smith embarked an investigative career that focused on fundamental studies of cell proliferation. While a postdoctoral fellow at L'Institut de Cancerologie et d'Immunogenetique in Villejuif France, he developed a quantitative assay for erythropoietin and first studied the suppressive effects of interferon on the proliferation of erythroid precurser cells [1]. Subsequently, while on the faculty at Dartmouth Medical School for 20 years, Dr. Smith focused on basic research into lymphocyte proliferation and how the immune system operates, and made several fundamental discoveries that transformed our understanding of immunity. Dr. Smith#146;s research team created the first antigen-specific monoclonal T lymphocytes, which revolutionized the study of T cells [2]. Among other things, this advance allowed them to develop the first quantitatiive bioassay for an interleukin, which then allowed them to discover, characterize and purify the interleukin 2 (IL2) molecule to homogeneity, the first interleukin molecule discovered [3]. They then showed that IL2 is the major growth factor (hormone) for mature T cells [4]. This discovery allowed them to demonstrate that IL1 and IL2 are distinct cytokines, thereby creating the interleukin nomenclature [5, 6]. They then went on to discover and characterize the IL2 receptor, which was the first interleukin receptor ever described [7]. Further research into the IL2-IL2 receptor interaction revealed that the cell determines to divide by counting the number of receptor #147;hits#148; delivered by IL2, and that this mechanism is responsible for exquisite growth control of normal cells [8]. The understanding that these discoveries provided, led Smith to move his research to New York, when he added clinical research to his fundamental efforts. Since 1994, Smith and his research group at Weill Cornell have focused on new approaches to augment immunity to treat chronic viral infections.
1. Smith KA, Fredrickson TN, Mobraaten LW, DeMaeyer E: The interaction of erythropoietin with fetal liver cells II. Inhibition of the erythropoietin effect by interferon. Exp Hematol 1977, 5:333-340.
2. Baker PE, Gillis S, Smith KA: Monoclonal cytolytic T-cell lines. J Exp Med 1979, 149:273-278.
3. Smith KA, Favata MF, Oroszlan S: Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics. J Immunol 1983, 131:1808-1815.
4. Smith KA: T-cell growth factor. Immunol Rev 1980, 51:337-357.
5. Smith KA, Gilbride KJ, Favata MF: Lymphocyte activating factor promotes T-cell growth factor production by cloned murine lymphoma cells. Nature 1980, 287:853-855.
6. Smith KA, Lachman LB, Oppenheim JJ, Favata MF: The functional relationship of the interleukins. J Exp Med 1980, 151:1551-1556.
7. Robb RJ, Munck A, Smith KA: T cell growth factor receptors: Quantitation, specificity, and biological relevance. J Exp Med 1981, 154:1455-1474.
8. Cantrell DA, Smith KA: The interleukin-2 T-cell system: a new cell growth model. Science 1984, 224:1312-1316.
