The metamorphosis of immunology from a curiosity of medicine associated with vaccination to a modern science focused at the center of basic research in molecular medicine is chronicled here. The people and events that led to this development are no less fascinating than the subject itself. A great number of researchers in diverse areas of medicine and science contributed to building the body of knowledge we now possess. It is possible to name only a few here, but we owe a debt to them all. We are standing on the shoulders of giants, and in remembering their achievements we come to understand better the richness of our inheritance.
Resistance against infectious disease agents was the principal concern of bacteriologists and pathologists establishing the basis of classical immunology in the latter half of the 19th and early 20th centuries. Variolation was practiced for many years prior to Edward Jenner's famous studies proving that inoculation with cowpox could protect against subsequent exposure to smallpox. This established him as the founder of immunology. He contributed the first reliable method of conferring lasting immunity to a major contagious disease. Following the investigations by Louis Pasteur on immunization against anthrax, chicken cholera, and rabies, and Robert Koch's studies on hypersensitivity in tuberculosis, their disciples continued research on immunity against infectious disease agents. Emil von Behring and Paul Ehrlich developed antitoxin against diphtheria, while Elie Metchnikoff studied phagocytosis and cellular reactions in immunity. Hans Buchner described a principle in the blood later identified by Jules Bordet as alexine or complement. Bordet and Octave Gengou went on to develop the complement fixation test that was useful to assay antigen-antibody reactions. Karl Landsteiner described the ABO blood groups of man in 1900, followed by his elegant studies establishing the immunochemical basis of antigenic specificity.
Charles Robert Richet and Paul Jules Portier in the early 1900s attempted to immunize dogs against toxins in the tentacles of sea anemones but inadvertently induced a state of hypersusceptibility, which they termed anaphylaxis. Since that time, many other hypersensitivity and allergic phenomena that are closely related to immune reactions have been described. Four types of hypersensitivity reactions are now recognized as contributory mechanisms in the production of immunological diseases. From the early 1900s until the 1940s, immunochemistry was a predominant force maintaining that antibody was formed through a template mechanism. With the discovery of immunological tolerance by Peter Medawar in the 1940s, David Tal-mage's cell selection theory, and Frank M. Burnet's clonal selection theory of acquired immunity, it became apparent that a selective theory based on genetics was more commensurate with the facts than was the earlier template theory of the immunochemists. With the elucidation of immunoglobulin structure by Rodney Robert Porter and Gerald Edelman, among others, in the late 1950s and 1960s, modern immunology emerged at the frontier of medical research. Jean Baptiste Dausset described human histocompatibility antigens, and transplantation immunology developed into a major science, making possible the successful transplantation of organs. Bone marrow transplants became an effective treatment for severe combined immunodeficiency and related disorders. The year 1960 marked the beginning of a renaissance in cellular immunology, and the modern era dates from that time. Many subspecialties of immunology are now recognized and include such diverse topics as molecular immunology (immunochemistry), immunobiology, immunogenetics, immunopathology, tumor immunology, transplantation, comparative immunology, immunotoxicology, and immu-nopharmacology. Thus, it is apparent that immunology is only at the end of the beginning and has bright prospects for the future as evidenced by the exponential increase in immunologic literature in recent years.
In 1948, Astrid Elsa Fagraeus established the role of the plasma cell in antibody formation. The fluorescence antibody technique developed by Albert Coons was a major breakthrough for the identification of antigen in tissues and subsequently demonstrated antibody synthesis by individual cells. While attempting to immunize chickens in which the bursa of Fabricius had been removed, Bruce Glick et al. noted that antibody production did not take place. This was the first evidence of bursa-dependent antibody formation. Robert A. Good immediately realized the significance of this finding for immunodeficiencies of childhood. He and his associates in Minneapolis and J.F.A.P. Miller in England went on to show the role of the thymus in the immune response, and various investigators began to search for bursa equivalence in man and other animals. Thus, the immune system of many species was found to have distinct bursa-dependent, antibody-synthesizing, and thymus-dependent cell-mediated limbs. In 1959, James Gowans proved that lymphocytes actually recirculate. In 1966, Tzvee Nicholas Harris et al. demonstrated clearly that lymphocytes could form antibodies. In 1966 and 1967, Claman et al., David et al., and Mitchison et al. showed that T and B lymphocytes cooperate with one another in the production of an immune response. Various phenomena such as the switch from forming one class of immunoglo-bulin to another by B cells were demonstrated to be dependent upon a signal from T cells activating B cells to change from IgM to IgG or IgA production. B cells stimulated by antigen in which no T cell signal was given continued to produce IgM antibody. Such antigens were referred to as thymus-independent antigens, and others requiring T cell participation as thymus-dependent antigens. Mitchison et al. described a subset of T lymphocytes demonstrating helper activity, i.e., helper T cells. In 1971, Gershon and Condo described suppressor T cells. Suppressor T cells have been the subject of much investigation but have eluded confirmation by the techniques of molecular biology. Baruj Benacerraf et al. demonstrated the significant role played by gene products of the major histocompatibility complex in the specificity and regulation of T cell-dependent immune response. Jerne described the network theory of immunity in which antibodies formed against idiotypic specificities of antibody molecules followed by the formation of antiidiotypic antibodies constitutes a significant additional immunoreg-ulatory process for immune system function. This postulate has been proved valid by numerous investigators. Tonegawa et al. and Leder et al. identified and cloned the genes that code for variable and constant diversity in antibody-combining sites. In 1975, George Kohler and Cesar Milstein successfully produced monoclonal antibodies by hybridizing mutant myeloma cells with antibody-producing B cells (hybridoma technique). The B cells conferred the antibody-producing capacity while the myeloma cells provided the capability for endless reproduction. Monoclonal antibodies are the valuable homogeneous products of hybridomas that have widespread application in diagnostic laboratory medicine.
Rhazes (Abu Bakr Muhammad ibn Zakariya) (865-932) Persian philosopher and alchemist who described measles and smallpox as different diseases. He also was a proponent of the theory that immunity is acquired. Rhazes is often cited as the premier physician of Islam.
Girolamo Fracastoro (1478-1553) A physician who was born in Verona and educated in Padua. His interests ranged from poetry to geography. He proposed the theory of acquired immunity and was a leader in the early theories of contagion. Syphilis sive Morbus Gallicus, 1530; De Sympathia et Antipathia Rerum, 1546; De Contagione, 1546.
Smallpox cartoon, artist unknown, from the Clement C. Fry collection. Yale Medical Library, contributed by Jason S. Zielonka, published in J. Hist. Med. 27:447, 1972. Legend translated: smallpox-disfigured father says, "How shameful that your pretty little children should call my children stupid and should run away, refusing to play with them as friends " Meanwhile, the children lament: "Father dear, it appears to be your fault that they're avoiding us. To tell the truth, it looks as though you should have inoculated us against smallpox."
Lady Mary Wortley Montagu (1689-1762) Often credited as the first to introduce inoculation as a means of preventing smallpox in England in 1722. After observing the practice in Turkey where her husband was posted as Ambassador to the Turkish Court, she had both her young son and daughter inoculated and interested the Prince and Princess of Wales in the practice. Accounts of inoculation against smallpox are found in her Letters, 1777. Robert Halsband authored a biography, The Life of Lady Mary Wortley Montagu, Clarendon, Oxford, 1956.
Edward Jenner (1749-1822) Often termed the founder of immunology for his contribution of the first reliable method of providing lasting immunity to a major contagious disease. He studied medicine under John Hunter and for most of his career was a country doctor in Berkeley in southern England. It was common knowledge in the country that an eruptive skin disease of cattle (cowpox) and a similar disease in horses called "grease" conferred immunity to smallpox on those who cared for the animals and caught the infection from them. Jenner carefully observed and recorded 23 cases. The results of his experiments were published, establishing his claim of credit for initiating the technique of vaccination. He vaccinated an 8-year-old boy, James Phipps, with matter taken from the arm of the milkmaid, Sara Nelmes, who was suffering from cowpox. After the infection subsided, he inoculated the child with smallpox and found that the inoculation had no effect. His results led to widespread adoption of vaccination in England and elsewhere in the world, ultimately leading to eradication of smallpox.
Louis Pasteur (1822-1895) French. Father of immunology. One of the most productive scientists of modern times, Pasteur's contributions included the crystallization of l- and o-tartaric acid disproving the theory of spontaneous generation, and studies of diseases in wine, beer, and silkworms. He successfully immunized sheep and cattle against anthrax, terming the technique "vaccination" in honor of Jenner. He used attenuated bacteria and viruses for vaccination. Pasteur produced a vaccine for rabies by drying the spinal cord of rabbits and using the material to prepare a series of 14 injections of increasing virulence. A child's life (Joseph Meister) was saved by this treatment. Les Maladies des Vers a Soie, 1865; Etudes sur le Vin, 1866; Etudes sur la Biere, 1876; Oeuvres, 1922-1939.
Julius Cohnheim (1839-1884) German experimental pathologist who was the first proponent of inflammation as a vascular phenomenon. Lectures on General Pathology, 1889.
Heinrich Hermann Robert Koch (1843-1910) German bacteriologist awarded the Nobel Prize in 1905 for his work on tuberculosis. Koch made many contributions to the field of bacteriology. Along with his postulates for proof of etiology, Koch instituted strict isolation and culture methods in bacteriology. He studied the life cycle of anthrax and discovered both the Vibrio cholerae and the tubercle bacillus. The Koch phenomenon and Koch-Weeks bacillus both bear his name.
Elie Metchnikoff (1845-1916) Born at Ivanovska, Ukraine, where he was a student of zoology with a very special interest in comparative embryology. He earned a Ph.D. degree at the University of Odessa where he also served as professor of zoology. He studied phagocytic cells of starfish larvae in 1884 in a marine laboratory in Italy. This served as the basis for his cellular phagocytic theory of immunity. On leaving Russia for political reasons, he accepted a position at the Institut Pasteur in Paris where he extended his work on the defensive role of phagocytes and championed his cellular theory of immunity. He also made numerous contributions to immunology and bacteriology. He shared the 1908 Nobel Prize in Physiology or Medicine with Paul Ehrlich "in recognition for their work on immunity." Lecons sur le Pathologie de l'Inflammation, 1892; L'Immunite dans les Maladies Infectieuses, 1901; Etudes sur la Nature Humaine, 1903.
Alexandre Besredka (1870-1940) Parisian immunologist who worked with Metchnikoff at the Pasteur Institute. He was born in Odessa. He contributed to studies of local immunity, anaphylaxis, and antianaphylaxis. Anaphylaxie et Antianaphylaxie, 1918; Histoire d'une Idee: L'Oeuvre de Metchnikoff, 1921; Etudes sur l'Immunite dans les Maladies Infectieuses, 1928.
Paul Ehrlich (1854-1915) Born in Silesia, Germany, and graduated as a doctor of medicine from the University of Leipzig. His scientific work included three areas of investigation. He first became interested in stains for tissues and cells and perfected some of the best ones to demonstrate the tubercle bacillus and leukocytes in blood. His first immunological studies were begun in 1890 when he was an assistant at the Institute for Infectious Disease under Robert Koch. After first studying the antibody response to the plant toxins abrin and ricin, Ehrlich published the first practical technique to standardize diphtheria toxin and antitoxin preparations in 1897. He proposed the first selective theory of antibody formation known as the "side chain theory" which stimulated much research by his colleagues in an attempt to disprove it. He served as director of his own institute in Frankfurt-am-Main where he published papers with a number of gifted colleagues, including Dr. Julius Morgenroth, on immune hemolysis and other immunological subjects. He also conducted a number of studies on cancer and devoted the final phase of his career to the development of chemotherapeutic agents for the treatment of disease. He shared the 1908 Nobel Prize with Metchnikoff for their studies on immunity. Fruits of these labors led to treatments for trypanosomiasis and syphilis (Salvarsan, "the magic bullet"). Collected Studies on Immunity, 1906; Collected Papers of Paul Ehrlich, 3 vols., 1957.
August von Wassermann (1866-1925) German physician who, with Neisser and Bruck, described the first serological test for syphilis, i.e., the Wassermann reaction. Handbook der Pathogenen Mikroorganismen (with Kolle), 1903.
Hans Buchner (1850-1902) German bacteriologist who was a professor of hygiene in Munich in 1894. He discovered complement. Through his studies of normal serum and its bactericidal effects, he became an advocate of the humoral theory of immunity.
Svante Arrhenius (1859-1927) Photographed with Paul Ehrlich, 1903. Coined the term "immunochemistry" and hypothesized that antigen-antibody complexes are reversible. He was awarded the Nobel Prize in Chemistry, 1903. Immunochemistry, 1907.
Ehrlich side chain theory The first selective theory of antibody synthesis developed by Paul Ehrlich in 1900. Although elaborate in detail, the essential feature of the theory was that cells of the immune system possess the genetic capability to react to all known antigens and that each cell on the surface bears receptors with surface haptophore side chains. On combination with antigen, the side chains would be cast off into the circulation and new receptors would replace the old ones. These cast-off receptors represented antibody molecules in the circulation. Although far more complex than this explanation, the importance of the theory was in the amount of research stimulated to try to disprove it. Nevertheless, it was the first effort to account for the importance of genetics in immune responsiveness at a time when Mendel's basic studies had not even yet been "rediscovered" by De Vries.
Jules Jean Baptiste Vincent Bordet (1870-1961) Belgian physician who graduated with a doctor of medicine degree from the University of Brussels. He was preparateur in Metchnikoff's laboratory at the Institut Pasteur from 1894 to 1901, where he discovered immune hemolysis and elucidated the mechanisms of complement-mediated bacterial lysis. He and Gengou described complement fixation and pointed to its use in the diagnosis of infectious diseases. Their technique was subsequently used by von Wassermann to develop a complement-fixation test for syphilis which enjoyed worldwide popularity. His debates with Paul Ehrlich on the nature of antigen-antibody-complement interactions stimulated much useful research. He was awarded the Nobel Prize in Physiology or Medicine for his studies on immunity, 1919. Traite de l'Immunité dans les Maladies Infectieuses, 1920.
Emil Adolph von Behring (1854-1917) German bacteriologist who worked at the Institute for Infectious Disease in Berlin with Kitasato and Wernicke from 1890 to 1892 and demonstrated that circulating antitoxins against diphtheria and tetanus conferred immunity. He demonstrated that the passive administration of antitoxin, i.e., serum containing antitoxin could facilitate recovery. This represented the beginning of serum therapy, especially for diphtheria. He received the first Nobel Prize in Physiology or Medicine in 1901 for this work. Die Blutserumtherapie, 1902; Gesammelte Abhandlungen, 1915; Behring, Gestalt und Werk, 1940; Emil von Behring zum Gedachtnis, 1942.
Shibasaburo Kitasato (1892-1931) Codiscoverer with Emil von Behring of antitoxin antibodies.
Karl Landsteiner (1868-1943) Viennese pathologist and immunologist who later worked at the Rockefeller Institute for Medical Research in New York. Received the Nobel Prize in 1930 "for his discovery of the human blood groups." He was the first to infect monkeys with poliomyelitis and syphilis to allow controlled studies of these diseases. He established the immu-nochemical specificity of synthetic antigens and haptens. Landsteiner felt his most important contribution was in the area of antibody-hapten interactions. Die Spezifizität der serologiochen Reaktionen, 1933; The Specificity of Serological Reactions, 1945.
Charles Robert Richet (1850-1935) Parisian physician who became professor of physiology at the University of Paris. He was interested in the physiology of toxins and, with Portier, discovered anaphylaxis, for which he was awarded the Nobel Prize in Physiology or Medicine in 1913. He and Portier discovered anaphylaxis in dogs exposed to the toxins of murine invertebrates to which they had been previously sensitized. Thus, an immune-type reaction that was harmful rather than protective was demonstrated. Experimental anaphylaxis was later shown to be similar to certain types of hypersensitivity, which lent clinical as well as theoretical significance to the discovery. L'Anaphylaxie, 1911.
Paul Jules Portier (1866-1962) French physiologist who, with Richet, was the first to describe anaphylaxis.
Clemens Freiherr von Pirquet (1874-1929) Viennese physician who coined the term "allergy" and described serum sickness and its pathogenesis. He also developed a skin test for tuberculosis. He held academic appointments at Vienna, Johns Hopkins, and Breslau, and returned to Vienna in 1911 as director of the University Children's Clinic. Die Serumkrenkheit (with Schick), 1905; Klinische Studien über Vakzination und Vakzinale Allergie, 1907; Allergy, 1911.
Gaston Ramon (1886-1963) French immunologist who perfected the flocculation assay for diphtheria toxin.
Bela Schick (1877-1967) Austro-Hungarian pediatrician whose work with von Pirquet resulted in the discovery and description of serum sickness. He developed the test for diphtheria that bears his name. Die Serumkrankheit (with Pirquet), 1905.
Arthur Fernandez Coca (1875-1959) American allergist and immunologist. He was a major force in allergy and immunology. He named atopic antibodies and was a pioneer in the isolation of allergens. Together with Robert A. Cooke, Coca classified allergies in humans.
Robert Anderson Cooke (1880-1960) American immunologist and allergist who was instrumental in the founding of several allergy societies. With Coca he classified allergies in humans. Cooke also pioneered skin test methods and desensitization techniques.
Felix Haurowitz (1896-1988) A noted protein chemist from Prague who later came to the U.S. He investigated the chemistry of hemoglobins. In 1930 (with Breinl) he advanced the instruction theory of antibody formation. Chemistry and Biology of Proteins, 1950; Immunochemistry and Biosynthesis of Antibodies, 1968.
Jacques Oudin (1908-1986) French immunologist who was director of analytical immunology at the Pasteur Institute, Paris. His accomplishments include discovery of idiotypy and the agar single diffusion method antigen-antibody assay.
Almroth Edward Wright (1861-1947) British pathologist and immunologist who graduated with a doctor of medicine degree from Trinity College, Dublin, in 1889. He became professor of pathology at the Army Medical School in Netley in 1892. He became associated with the Institute of Pathology at St. Mary's Hospital Medical School, London, in 1902. Together with Douglas, he formulated a theory of opsonins and perfected an antitoxoid inoculation system. Wright studied immunology in Frankfurt-am-Main under Paul Ehrlich and made important contributions to the immunology of infectious diseases and immunization. He played a significant role in the founding of the American Association of Immunologists. His published works include Pathology and Treatment of War Wounds, 1942; Researches in Clinical Physiology, 1943; Studies in Immunology, 2 vols., 1944.
Carl Prausnitz-Giles (1876-1963) German physician from Breslau who conducted extensive research on allergies. He and Kustner successfully transferred food allergy with serum. This became the basis for the Prausnitz-Kustner test. He worked at the State Institute for Hygiene in Breslau and spent time at the Royal Institute for Public Health in London earlier in the century. In 1933, he left Germany to practice medicine on the Isle of Wight.
Nicolas Maurice Arthus (1862-1945) Paris physician. He studied venoms and their physiological effects; he was the first to describe local anaphylaxis (the Arthus reaction) in 1903. Arthus investigated the local necrotic lesion resulting from a local antigen-antibody reaction in an immunized animal. De l'Anaphylaxie a l'Immunite, 1921.
Albert Calmette (1863-1933) French physician who was subdirector of the Institut Pasteur in Paris. In a popular book published in 1920, Bacillary Infection and Tuberculosis, he emphasized the necessity of separating tuberculin reactivity from anaphylaxis. Together with Guerin, he perfected BCG vaccine and also investigated snake venom and plague serum.
Michael Heidelberger (1888-1991) American; a founder of immunochemistry. He began his career as an organic chemist. His contributions to immunology include the perfection of quantitative immunochemical methods and the immunochemical characterization of pneumococcal polysaccharides. Heidelberger's contributions to immunologic research are legion. During his career he received the Lasker Award, the National Medal of Science, the Behring Award, the Pasteur Medal, and the French Legion of Honor. Lectures on Immunochemistry, 1956.
Arne W. Tiselius (1902-1971) Swedish chemist who was educated at the University of Uppsala where he also worked in research. In 1934, he was at the Institute for Advanced Study in Princeton, worked for the Swedish National Research Council in 1946, and became president of the Nobel Foundation in 1960. Awarded the Nobel Prize in Chemistry in 1948, together with Elvin A. Kabat he perfected the electrophoresis technique and classified antibodies as y globulins. He also developed synthetic blood plasmas.
Elvin Abraham Kabat (1914-2000) American immunochemist. With Tise-lius he was the first to separate immunoglobulins electrophoretically. He also demonstrated that y globulins can be distinguished as 7S or 19S. Other contributions include research on antibodies to carbohydrates, the antibody combining site, and the discovery of immunoglobulin chain variable regions. He received the National Medal of Science. Experimental Immunochemistry (with Mayer), 1948; Blood Group Substances: Their Chemistry and Immu-nochemistry; Structural Concepts in Immunology and Immunochemistry, 1956.
Henry Hallett Dale (1875-1968) British investigator who made a wide range of scientific contributions including work on the chemistry of nerve impulse transmissions, the discovery of histamine, and the development of the Schultz-Dale test for anaphylaxis. He received a Nobel Prize in 1935.
John Richardson Marrack (1899-1976) British physician who served as professor of chemical pathology at Cambridge and at London Hospital. He hypothesized that antibodies are bivalent, labeled antibodies with colored dyes, and proposed a lattice theory of antigen-antibody complex formation in fundamental physicochemical studies.
William Dameshek (1900-1969) Noted Russian-American hematologist who was among the first to understand autoimmune hemolytic anemias. He spent many years as editor-in-chief of the journal Blood.
Orjan Thomas Gunnersson Ouchterlony (1914- ) Swedish bacteriologist who developed the antibody detection test that bears his name. Two-dimensional double diffusion with subsequent precipitation patterns is the basis of the assay. Handbook of Immunodiffusion and Immunoelectrophoresis, 1968.
Merrill Chase (1905- ) American immunologist who worked with Karl Landsteiner at the Rockefeller Institute for Medical Research, New York. He investigated hypersensitivity, including delayed type hypersensitivity and contact dermatitis. He was the first to demonstrate the passive transfer of tuberculin and contact hypersensitivity and also made contributions in the fields of adjuvants and quantitative methods.
Philip Levine (1900-1987) Russian-American immunohematologist. With Landsteiner, he conducted pioneering research on blood group antigens, including discovery of the MNP system. His work contributed much to transfusion medicine and transplantation immunobiology.
Jules Freund (1890-1960) Hungarian physician who later worked in the U.S. He made many contributions to immunology, including work on antibody formation, studies on allergic encephalomyelitis, and the development of Freund's adjuvant. He received the Lasker Award in 1959.
Hans Zinsser (1878-1940) A leading American bacteriologist and a Columbia, Stanford, and Harvard educator whose work in immunology included hyper-sensitivity research and plague immunology, formulation of the unitarian theory of antibodies, and demonstration of differences between tuberculin and ana-phylactic hypersensitivity. His famous text, Microbiology (with Hiss), 1911, has been through two dozen editions since its first appearance.
Max Theiler (1899-1972) South African virologist who received the Nobel Prize in 1951 "for his development of vaccines against yellow fever."
Gregory Shwartzman (1896-1965) Russian-American microbiologist who described local and systemic reactions that follow injection of bacterial endo-toxins. The systemic Shwartzman reaction, a nonimmunologic phenomenon, is related to disseminated intravascular coagulation. The local Shwartzman reaction in skin resembles the immunologically based Arthus reaction in appearance. Phenomenon of Local Tissue Reactivity and Its Immunological and Clinical Significance, 1937.
Robin Coombs (1921- ) British pathologist and immunologist who is best known for the Coombs' test as a means for detecting immunoglobulin on the surface of a patient's red blood cells. The test was developed in the 1940s to demonstrate autoantibodies on the surface of red blood cells that failed to cause agglutination of these erythrocytes. It is a test for autoimmune hemolytic anemia. He also contributed much to serology, immunohematol-ogy, and immunopathology. The Serology of Conglutination and Its Relation to Disease, 1961; Clinical Aspects of Immunology (with Gell), 1963.
Albert Hewett Coons (1912-1978) American immunologist and bacteriologist who was an early leader in immunohistochemistry with the development of fluorescent antibodies. Coons received the Lasker medal in 1959, the Ehrlich prize in 1961, and the Behring prize in 1966.
Pierre Grabar (1898-1986) French-educated immunologist, born in Kiev, who served as chef de service at the Institut Pasteur and as director of the National Center for Scientific Research, Paris. Best known for his work with Williams in the development of immunoelectrophoresis. He studied antigen-antibody interactions and developed the "carrier" theory of antibody function. He was instrumental in reviving European immunology in the era after World War II.
Herman Nathaniel Eisen (1918- ) American physician whose research contributions range from equilibrium dialysis (with Karush) to the mechanism of contact dermatitis.
Milan Hasek (1925-1985) Czechoslovakian scientist whose contributions to immunology include investigations of immunologic tolerance and the development of chick embryo parabiosis. Hasek also made fundamental contributions to transplantation biology.
Gustav Joseph Victor Nossal (1931- ) Australian immunologist whose seminal works have concentrated on antibodies and their formation. He served as director of the Walter and Eliza Hall Institute of Medical Research in Melbourne.
Antibodies and Immunity, 1969; Antigens, Lymphoid Cells and the Immune Response (with Ada), 1971.
Ernest Witebsky (1901-1969) German-American immunologist and bacteriologist who made significant contributions to transfusion medicine and to concepts of autoimmune diseases. He was a direct descendent of the Ehrlich school of immunology, having worked at Heidelberg with Hans Sachs, Ehrlich's principal assistant, in 1929. He came to Mt. Sinai Hospital in New York in 1934 and became professor at the University of Buffalo in 1936, where he remained until his death. A major portion of his work on autoimmunity was the demonstration, with Noel R. Rose, of experimental autoimmune thyroiditis.
Noel Richard Rose (1927- ) American immunologist and authority on autoimmune diseases who first discovered, with Witebsky, experimental autoimmune thyroiditis. His subsequent contributions to immunology are legion. He has authored numerous books and edited leading journals in the field.
Peter Alfred Gorer (1897-1961) British pathologist who was professor at Guy's Hospital Medical School, London, where he made major discoveries in transplantation genetics. With Snell, he discovered the H-2 murine histocompatibility complex. Most of his work was in transplantation genetics. He identified antigen II and described its association with tumor rejection. The Gorer Symposium, 1985.
Peter Brian Medawar (1915-1987) British transplantation biologist who earned his Ph.D. at Oxford in 1935, where he served as lecturer in zoology. He was subsequently a professor of zoology at Birmingham (1947) and at University College, London, in 1951. He became director of the Medical Research Council in 1962 and of the Clinical Research Center at Northwick Park in 1971. Together with Billingham and Brent, he made seminal discoveries in transplantation. He shared the 1960 Nobel Prize in Physiology or Medicine with Sir MacFarlane Burnet.
Ray David Owen (1915- ) American geneticist who described erythrocyte mosaicism in dizygotic cattle twins. This discovery of reciprocal erythrocyte tolerance contributed to the concept of immunologic tolerance. The observation that cattle twins, which shared a common fetal circulation, were chimeras and could not reject transplants of each other's tissues later in life provided the groundwork for Burnet's ideas about tolerance and Medawar's work in transplantation.
Frank James Dixon (1920- ) American physician and researcher noted for his fundamental contributions to immunopathology that include the role of immune complexes in the production of disease. He is also known for his work on antibody formation. Dixon was the founding director of the Research Institute of Scripps Clinic, La Jolla, CA.
Niels Kaj Jerne (1911-1994) Immunologist, born in London and educated at Leiden and Copenhagen, who shared the Nobel Prize in 1984 with Kohler and Milstein for his contributions to immune system theory. These include his selective theory of antibody formation, the functional network of interacting antibodies and lymphocytes, and distinction of self from nonself by T lymphocytes. He studied antibody synthesis and avidity, perfected the hemolytic plaque assay, developed natural selection theory of antibody formation, and formulated the idiotypic network theory. He was named director of the Paul Ehrlich Institute in Frankfurt-am-Main in 1966 and director of the Basel Institute for Immunology in 1969.
David Wilson Talmage (1919- ) American physician and investigator who in 1956 developed the cell selection theory of antibody formation. His work was a foundation for Burnet's subsequent clonal selection theory. After training in immunology with Taliaferro in Chicago where he became a professor in 1952, Talmage subsequently became chairman of microbiology in 1963, dean of medicine in 1968, and director of the Webb-Waring Institute in Denver in 1973. In addition to his investigations of antibody formation, he also studied heart transplantation tolerance. The Chemistry of Immunity in Health and Disease (with Cann), 1961.
Joshua Lederberg (1925- ) American biochemist who made a significant contribution to immunology with his work on the clonal selection theory of antibody formation. He received a Nobel Prize in 1958 (with Beadle and Tatum) for genetic recombination and organization of genetic material in bacteria.
Henry Sherwood Lawrence (1916- ) American immunologist. While studying type IV hypersensitivity and contact dermatitis, he discovered transfer factor. Cellular and Humoral Aspects of Delayed Hypersensitivity, 1959.
Jan Gosta Waldenstrom (1906-1996) Swedish physician who described macroglobulinemia, which now bears his name. He received the Gairdner Award in 1966.
Daniel Bovet (1907-1992) Primarily a pharmacologist and physiologist, Bovet received the Nobel Prize in 1957 for his contributions to the understanding of the role histamine plays in allergic reactions and the development of antihis-tamines. Structure Chimique et Activite Pharmacodynamique des Medicaments du Systeme Nerveux Vegetatif, 1948; Curare and Curare-Like Agents, 1959.
Frank MacFarlane Burnet (1899-1985) Australian virologist and immunologist who shared the Nobel Prize with Peter B. Medawar in 1960 for the discovery of acquired immunological tolerance. Burnet was a theoretician who made major contributions to the developing theories of self tolerance and clonal selection in antibody formation. Burnet and Fenner's suggested explanation of immunologic tolerance was tested by Medawar et al., who confirmed the hypothesis in 1953 using inbred strains of mice. Production of Antibodies (with Fenner), 1949; Natural History of Infectious Diseases, 1953; Clonal Selection Theory of Antibody Formation, 1959; Autoimmune Diseases (with Mackay), 1962; Cellular Immunology, 1969; Changing Patterns (autobiography), 1969.
George Davis Snell (1903-1996) American geneticist who shared the 1980 Nobel Prize in Physiology or Medicine with Jean Dausset and Baruj Benacerraf "for their work on genetically determined structures of the cell surface that regulate immunologic reactions." Snell's major contributions were in the field of mouse genetics including discovery of the H-2 locus and the development of congenic mice. He made many seminal contributions to transplantation genetics and received the Gairdner Award in 1976. Histocompatibility (with Dausset and Nathenson), 1976.
Jean Baptiste Gabriel Dausset (1916- ) French physician and investigator. He pioneered research on the HLA system and the immuno-genetics of histocompatibility. For this work, he shared a Nobel Prize with Benacerraf and Snell in 1980. He made numerous discoveries in immunogenetics and transplantation biology. Immunohematologie, Biologique et Clinique, 1956; HLA and Disease (with Svejaard), 1977.
Baruj Benacerraf (1920- ) American immunologist born in Caracas, Venezuela. His multiple contributions include the carrier effect in delayed hypersensitivity, lymphocyte subsets, MHC, and Ir immunogenetics, for which he shared the Nobel Prize in 1980 with Jean Dausset and George Snell. Benacerraf et al. demonstrated that immune response Ir genes control an animal's response to a given antigen. These genes were localized in the I region of the MHC. Textbook of Immunology (with E. Unanue), 1979.
Henry George Kunkel (1916-1983) American physician and immunologist. The primary focus of his work was immunoglobulins. He characterized myeloma proteins as immunoglobulins and rheumatoid factor as an autoan-tibody. He also discovered IgA and idiotypy and contributed to immunoglo-bulin structure and genetics. Kunkel received the Lasker Award and the Gairdner Award. A graduate of Johns Hopkins Medical School, he served as professor of medicine at the Rockefeller Institute for Medical Research.
AstridElsa Fagraeus-Wallbom (1913- ) Swedish investigator noted for her doctoral thesis which provided the first clear evidence that immunoglobulins are made in plasma cells. In 1962, she became chief of the Virus Department of the National Bacteriological Laboratory, and in 1965, professor of immunology at the Karolinska Institute in Stockholm. She also investigated cell membrane antigens and contributed to the field of clinical immunology. Antibody Production in Relation to the Development of Plasma Cells, 1948.
Rosalyn Sussman Yalow (1921- ) American investigator who shared the 1977 Nobel Prize with Guillemin and Schally for her endocrinology research and perfection of the radioimmunoassay technique. With Berson, Yalow made an important discovery of the role antibodies play in insulin-resistant diabetes. Her technique provided a test to estimate nanogram or picogram quantities of various types of hormones and biologically active molecules, thereby advancing basic and clinical research.
J.F.A.P. Miller (1931- ) Proved the role of the thymus in immunity while investigating gross leukemia in neonatal mice.
Robert Alan Good (1922-2003) American immunologist and pediatrician who has made major contributions to studies on the ontogeny and phylogeny of the immune response. Much of his work focused on the role of the thymus and the bursa of Fabricius in immunity. He and his colleagues demonstrated the role of the thymus in the education of lymphocytes. The Thymus in Immunobiology, 1964; Phylogeny of Immunity, 1966.
James Gowans (1924- ) British physician and investigator whose principal contribution to immunology was the demonstration that lymphocytes recirculate via the thoracic duct, which radically changed understanding of the role lymphocytes play in immune reactions. He also investigated lymphocyte function. Gowans was made director of the MRC Cellular Immunobiology Unit, Oxford, in 1963.
Rodney Robert Porter (1917-1985) British biochemist who received the Nobel Prize in 1972, with Gerald Edelman, for their studies of antibodies and their chemical structure. Porter cleaved antibody molecules with the enzyme papain to yield Fab and Fc fragments. He suggested that antibodies have a four-chain structure. Fab fragments were shown to have the antigen-binding sites, whereas the Fc fragment conferred the antibody's biological properties. He also investigated the sequence of complement genes in the MHC. Defense and Recognition, 1973.
Gerald Maurice Edelman (1929- ) American investigator who was professor at the Rockefeller University and shared the Nobel Prize in 1972 with Porter for their work on antibody structure. Edelman was the first to demonstrate that immunoglobulins are composed of light and heavy polypeptide chains. He also did pioneering work with the Bence-Jones protein, cell adhesion molecules, immunoglobulin amino acid sequence, and neurobiology.
Richard K. Gershon (1932-1983) One of the first to demonstrate the suppressor role of the T cell. The suppressor T cell was described as a subpopulation of lymphocytes that diminish or suppress antibody formation by B cells or down-regulate the ability of T lymphocytes to mount a cellular immune response. The inability to confirm the presence of receptor molecules on their surface has cast a cloud over the suppressor cell; however, functional suppressor cell effects are indisputable.
Kimishige Ishizaka (1925- ) and Terako Ishizaka discovered IgE and have contributed to elucidation of its function.
Georges J.F. Kohler (1946-1995) German immunologist who shared the Nobel Prize in 1984 with Cesar Milstein for their work in the production of monoclonal antibodies by hybridizing mutant myeloma cells with antibody-producing B cells (hybridoma technique). Monoclonal antibodies have broad applications in both basic and clinical research as well as in diagnostic assays.
Cesar Milstein (1927-2002) Immunologist born in Argentina who worked in the U.K. He shared the 1984 Nobel Prize with Kohler for their production of monoclonal antibodies by hybridizing mutant myeloma cells with antibody-producing B cells (hybridoma technique). The production of monoclonal antibodies by hybridoma technology revolutionized immunological research.
Susumu Tonegawa (1939- ) Japanese-born immunologist working in the U.S. He received the Nobel Prize in 1987 for his research on immunoglobulin genes and antibody diversity. Tonegawa and many colleagues were responsible for the discovery of immunoglobulin gene C, V, J, and D regions and their rearrangement.
E. Donnall Thomas and Joseph E. Murray Recipients of the 1990 Nobel Prize for Physiology or Medicine for their work during the 1950s and 1960s on reducing the risk of organ rejection by the body's immune system. Murray performed the first successful organ transplant in the world, which was a kidney from one identical twin to another, at the Peter Bent Brigham Hospital in Boston in 1954. Two years later, Thomas was the first to perform a successful transplant of bone marrow, which he achieved by administering a drug that prevented rejection. The two doctors have made significant discoveries that "have enabled the development of organ and cell transplantation into a method for the treatment of human disease," said the Nobel Assembly in its citation for the prize.
Rolf Zinkernagel (right) (1944- ) and Peter Doherty (left) (1940- ) Recipients of the 1996 Nobel Prize for Physiology or Medicine for their demonstration of MHC restriction. In an investigation of how T lymphocytes protect mice against lymphocytic choriomeningitis virus (LCMV) infection, they found that T cells from mice infected by the virus killed only infected target cells expressing the same major histocompatibility complex (MHC) class I antigens but not those expressing a different MHC allele. In their study, murine cytotoxic T cells (CTL) would only lyse virus-infected target cells if the effector and target cells were H-2 compatible. This significant finding had broad implications, demonstrating that T cells did not recognize the virus directly but only in conjunction with MHC molecules.
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