I ntroduction and History of Immunology

1. Introduction and History of Immunology Yufang Shi, Ph.D. University Professor Department of Molecular Genetics, Microbiology and Immunology UMDNJ-Robert Wood Johnson Medical School January 21, 2009

2. UMDNJ Micr-6005: Current Concepts of Immunology Rutgers 16:681:543: Immunology (3 Credits) Textbook: Immunobiology 6th ed., by Janeway, Travers, Walport, & Shlomchik Time: Monday and Wednesday, 1:40 to 3:00 pm. Classroom: Room V-10, RWJMS Research Tower Coordinator: Yufang Shi, D.V.M., Ph.D. Phone: 732 235 4501; Fax: 732 235 4505 E-mail: shiyufang@gmail.com Administrative Contact: Your school administrators : Diane Murano (murano@biology.rutgers.edu), Tina Cicolella (cicoletm@umdnj.edu) Ellen Feibel feibelec@umdnj.edu (send your contact information) 732 235 5467 Andrew L'Huillier andrewlhu@gmail.com

3. What is the Immune System? Why are you interested in this course? Have you ever taken an immunology course?

4. Logistics For most lectures, handouts will be available in class. Slides will be on http://www2.umdnj.edu/mgenmweb/courses/ccimmu/index.htm?=7 Textbook is for reference only. There will be no lab practice. READING ASSIGNMENTS Individual lecturer assigns relevant reviews/peer-reviewed publications. Lectures are designed by the expertise of lecturers. The textbook may not adequately cover specific topics. Some information may not be on the handouts. Therefore, attending each lecture is strongly encouraged. Some materials will be available in the Office of the Department of Molecular Genetics, Microbiology and Immunology (7th floor Research Tower) for photocopying. EXAMINATIONS There are 2 exams: Midterm and Final. Exams are likely to be in the closed book format. If you have a conflict, please contact the course coordinator to reschedule. There are NO assignments for extra credits. GRADE DISTRIBUTION: Class participation 15% Midterm Exam 35% Final Exam 50% If the school is closed due to weather conditions, lectures missed will be made up by extending the following class for another 80 minutes.

9. History and Overview of Immunology Reading List: Chapter 2, History of Immunology, by P.M.H. Mazumdar, in Fundamental Immunology, Ed: WE Paul. 5th Edition, 2003 Silverstein AM. 2001. The end of immunology? Nat Immunol 2:893-895. Silverstein AM. 2003. Darwinism and immunology: from Metchnikoff to Burnet. Nat Immunol. 2003 Jan;4(1):3-6. Available for photocopying at the Office of Molecular Genetics, Microbiology and Immunology, Room 727.

10. Immunity • Law.Exemption from a service, obligation, or duty; • Freedom from liability to taxation, jurisdiction, etc.; • Privilege granted to an individual or a corporation conferring exemption from certain taxes, burdens, or duties. • Health. Nonsusceptibility (resistance) to the invasive or pathogenic effects of foreign microorganisms or to the toxic effect of antigenic substances • The term “immunity” was first used in 1775 by Van Sweiten, a Dutch physician, as“immunitas” to describe the effects induced by an early attempt at variolization.

11. Overview of Immune System • Innate Immunity: • Fast-acting • Less specific recognition • Early during evolution • e.g. phagocytes, barriers to infection such as skin and mucus surfaces • Adaptive Immunity: • Specificity • Distinguish antigens sometimes present from those always present • Memory and Recall • Cells of the immune system • Leukocytes originating from bone marrow hematopoietic stem cells • Communication with other systems • Endocrine system • Central nervous system • Skeletal system • Disruption of the Immune System • Allergy • Autoimmunity • Immunodeficiency Psychoneuroimmunology

12. Origin of Immune Cells Biocarta.com

13. Immune Responses

14. Immunology: to understand the resistance to re-infections • As early as 2000 BC, disease, pestilence, and epidemics were recorded in Egypt. • Until quite recently, disease was regarded as a punishment from God or gods. God struck down those with evil in their hearts, it was a penalty and the ultimate price was death. For those who survived, they had clearly seen the error of their ways, had repented and made their peace with God. Their return to the faith ensured their future lack of attack by the disease. With this approach to death and disease there was little chance of developing an understanding of the immune system. • BUT: Individuals having survived a disease might often be spared further involvement on the RETURN, a phenomenon known as IMMUNITY. This was recorded at least 25 centuries ago. In 430BC, a plague (the true pathogen is unknown) swept through Athens. Historian Thucydides documented in "History of the Peloponnesian war" that those who survived an attack did not experience the plague again.

15. Immunology ·There have been various theories to explain acquired immunity, the formal explanation was provided by Edward Jenner’s reinfection studies (1780’s) ·       The history of immunology is really slightly more than 100 years if you consider Louis Pasteur as the “Father of immunology” as some immunologists do. ·       Cellular immunology, the “real” history begins after the World War II (1939-1945), along with the development of transplantation and the “clonal selection theory” formulated by the Australian immunologist, Sir Frank Macfarlane Burnet. Before that, most studies focused on the chemistry of the specificity.

16. Smallpox Caused by the variola virus. It enters the body through the lungs and is carried in the blood to the internal organs and skin where it multiplies. It can kill 10 to 30% of the total population, the most feared and greatest killer in human history. The first recorded infection was in Egypt in 1350. The first real epidemic might have been much earlier. Leave sunken scars in skin in mild cases. In severe case, it causes blood poisoning, secondary infections or internal bleeding. There is no treatment. It affected societies dramatically. Prince William died at 11. Mozart, George Washington and Abraham Lincoln were all infected. Beauty decorations such as veils were believed to hide scars. Smallpox is the earliest disease found to induce lifelong immunity. Variolation is the form of vaccination. Stopped in 1972. Currently, there should be enough doses available in the US. Smallpox vaccine is the first vaccine to be used and the first vaccine to be discontinued. President Bush was immunized with smallpox vaccine on Dec. 21, 2002.

17. Early forms of smallpox vaccine---variolation "The Genius of China: 3000 Years of Science, Discoveries and Inventions", Simon and Schuster, New York, by Robert Temple, 1986 "The origins of inoculation against smallpox in China are somewhat mysterious. We know that the technique originated at the southern province of Szechuan. In the south-west of that province there is a famous mountain called O-Mei Shan which is known for its connection with both Buddhism and the native Chinese religion of Taoism. The Taoist alchemists who lived as hermits in the caves of that mountain possessed the secret of smallpox inoculation in the tenth century AD. How long before that they had it we shall never know. The technique first came to public attention when the eldest son of the Prime Minister Wang Tan (王旦, 957-1017) died of smallpox. Wang desperately wished to prevent its happening to other members of his family, so he summoned physicians, wise men and magicians from all over the Empire to try to find some remedy. One Taoist hermit came from O-Mei Shan, described variously as a 'holy physician', a 'numinous old woman' (in which case a nun), and a 'ouija board immortal' (ouija boards or planchettes were widely used in China, where whole books were written through 'spirit dictation'). This monk or nun brought the technique of inoculation and introduced it to the capital.... ”

18. ·  Song dynasty (960-1279), Chinese used "Yi Miao": wearing an infected person’s clothes who had just recently died. ·       Inoculation against smallpox in China did not become widely known and practiced until the period 1567-72. Vivid descriptions of the practice are recorded by Yu Chang in his book Miscellaneous Ideas in Medicine, of 1643.” ·         Ming dynasty (1368-1644), Variolation: inserting scabs from patients under the skin of healthy individuals or blowing dried scab material up the noses of the individuals with a silver tube ("Gan Miao": dry vaccine) or using water to make a paste from scabs to insert into the nostrils ("Shi Miao": wet vaccine). ·       A more systemic summary of the Chinese smallpox vaccination was done by Chang Yen in 1741 in his "Zhong Miao Xin Shu" (a new book about vaccination).

20. Smallpox Vaccination to Europe • ·         During the seventeenth century, the practice from China was slowly introduced into neighboring countries along with the “Silk Road”, and it was in Turkey that it came to the attention of Europeans. • English merchant John Lister reported the Chinese method to the Royal Society in 1700. • In pre-colonial India, “tika”, or dot, would be made on the sole of the foot by “tikadars”. • The wife of the British Ambassador to Constantinople (Istanbul), Lady Mary Wortley Montagu (1689-1762) allowed her family to be 'variolated' in 1718.

21. LADY MARY WORTLEY MONTAGU (1689-1762) • ·A famous poet • http://www.montaguemillennium.com/familyresearch/h_1762_mary.htm • · Herself a smallpox victim; Poem: THE SMALL-POX • In December 1715 smallpox ruined her good looks and left her without eyelashes and with deeply pitted skin • Lady Mary was the wife of the British Ambassador to Turkey (1716-1718). Learned how to variolate persons in Turkey and variolated her son in 1717 and her daughter in England in 1721. • · Although there was much resistance to the acceptance of this vaccination method and Lady Mary was heavily criticized by the higher society in England, the permission to vaccinate the children of the Prince and Princess of Wales in 1772 dramatically promoted the adaptation of this method in England and in other part of Europe. • ·  By the second half of the 18th century, Europe was being ravaged by smallpox epidemics. By this time, in rural England, it was noticed that women who milked cows were frequently spared clinical smallpox disease and several undocumented accounts suggest that the connection was made between contact with cowpox virus and protection from smallpox.

22. Edward Jenner • Born on May 17, 1749, in Berkeley, Gloucestershire, England, Died Jan. 26, 1823. • ·    As a teenager, while learning to be a physician, he heard a young farm girl tell a doctor that she could not contract smallpox because she had once had cowpox (a very mild disease). This started him thinking about a vaccine. • ·       After years of experimenting, on May 14, 1796, Edward Jenner carried out a famous experiment on a healthy 8-year-old boy, James Phipps, with cowpox. He took material from a burst pustule on the arm of Sarah Nelmes who had apparently contracted cowpox. He then deliberately exposed the boy to virulent variola virus two months later and found that the child was protected, showing only a mild inflammation around the site where the variola was injected. • ·        Some record shows that in 1789 he had already experimented vaccination on his own son, then aged one-and-a-half, with the swine pox, followed by conventional smallpox inoculation. • A CRIME?? Sarah Nelmes’ hand

23. Jenner wrote a paper in 1798 explaining his experiments, and wanted to report his first case study in the “Transactions of the Royal Society of London” His study was rejected. He then went to London to demonstrate his theory. No one would submit to his vaccination. Discouraged, Jenner returned to Berkeley. • ·       In 1801, Jenner published “The Origin of the Vaccine Inoculation” describing how cowpox virus was prepared and used to protect ("vaccinate") healthy persons against smallpox. Material used as the vaccine was prepared from the arm of a vaccinated child, thus the distribution of vaccine involved the transportation of vaccinated children all over Europe. Orphans were often used for this purpose. Eventually, material from infected cows was used directly as vaccine. By 1840, the British government had banned other preventive treatments against smallpox. • “Vaccination,” the word Jenner invented for his treatment (from the Latin, vacca, a cow), was adopted by Louis Pasteur for immunization against any disease.

24. An Inquiry into the causes and effects of the Variolae Vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire, and known by the name of the cow-pox Baxby D. 1999. Edward Jenner's Inquiry; a bicentenary analysis. Vaccine. 1999 Jan 28;17(4):301-7.

25. ·       The Franco-Prussian War (1870-71). Smallpox epidemic French army was not vaccinated; 23,400 died. German army was vaccinated; only 278 died. ·       1980: as a result of Jenner's discovery, the World Health Assembly officially declared "the world and its peoples" free from endemic smallpox. ·       1996: 200 th anniversary of Edward Jenner's first experimental vaccination The Scientists: http://www.the-scientist.com/1996/04/01/14/1/ ·Some people believe that Lord Jeffrey Amherst, Commander-in-Chief for America, may have used Smallpox Blankets against the Indians during the French-Indian war (1754-1763). First use of biological warfare???

26. The last reported case of smallpox, Ali Maakin, in the world was in Somalia, on October 26, 1977 ·       The last stocks of the smallpox virus were kept frozen in laboratories at the Centers for Disease Control and Prevention, in Atlanta, and the Russian State Research Center of Virology and Biotechnology, in Koltsovo, Russia. ·       First deliberate destruction of a species? ·       Monkeypox in Congo: a new threat? Between February 1996 and October 1997, there were 511 suspected cases of monkeypox in the Democratic Republic of the Congo (DRC, formerly Zaire). This outbreak, the largest ever, raised fears that the virus had mutated and become more infectious to humans.

27. Current Smallpox Vaccine It is live vaccinia virus. No longer produced in calves; is produced by a cultured human fibroblast in laboratories. Provides protection for about 10 years (only an estimate). The efficacy of vaccinia vaccine to prevent smallpox has never been measured precisely during controlled trials and the level of antibody required for protection against smallpox infection is unknown. Method: use a forked needle to repeatedly press into the skin of the upper arm. Adverse reaction rate: 250 per million (0.025%)

28. “The development of a science depends on the thoughts and interactions of successive generations of scientists; by their work, these scientists uncover additional phenomena and facts, expanding the territory and the number of problems to be considered…” --Jerne, Basel Institue for Immunology, Basel, Switzerland. Development of Ideas in Immunology Aims Peroids Pioneers Notions Applications 1870-1890 Pasture & Metchnikoff Immunization & Phagocytosis Description 1890-1910 Behring & Ehrlich Antibodies & Cell Receptors 1910-1930 Bordet & Landsteiner Specificity & Haptens Mechanisms 1930-1950 Subcellular Ab synthesis & Ag temp. 1950-1970 Cellular Clonal selection Systemic Analysis 1970-1983 Multicellular Network Cooperation Immune regulation Modern Immunol. 1983-present Post-TCR Era Molecular Mechanisms

29. Louis Pasteur (1822-1895) Stereochemistist: molecular asymmetry Fermentation and silk worker disease, Pasteurisation , Germ Theory of disease Thus started microbilogy Attenuated vaccines for cholera, anthrax, and rabies On July 4, 1886, 9-year-old Joseph Meister was bitten repeatedly by a rabid dog. Pasteur treated him with his attenuated rabies vaccine two days later. Meister survived. Joseph Meister later become a gatekeeper for the Pasteur Institute. In 1940, when he was ordered by the German occupiers to open Pasteur's crypt, Joseph Meister refused and committed suicide! ·  Another way to look at Louis Pasteur: THE DREAM AND LIE OF LOUIS PASTEUR by R. B. Pearson http://whale.to/a/b/pearson.html

30. Pasteur’s contributions ·First, championed changes in hospital practices to minimize the spread of disease by microbes. ·       Second, discovered that weakened forms of a microbe could be used to immunize against more virulent forms of the microbe. ·       Third, found that rabies was transmitted by agents so small they could not be seen under a microscope, thus revealing the world of viruses. As a result he developed techniques to vaccinate dogs against rabies, and to treat humans bitten by rabid dogs. ·       And fourth, developed "pasteurization," a process by which harmful microbes in perishable food products are destroyed by heat, without destroying the food.

31. Robert Koch (1843-1910) ·German physician; also started to work on Anthrax in 1870's. Identified the spore stage.First time the causative agent of an infectious disease was identified. ·Koch's postulates: conditions that must be satisfied before accepting that particular bacteria cause particular diseases. ·Discovered the tubercle bacillus and tuberculin. Detailed tuberculin skin test (DTH). Awarded 1905 Nobel Prize.

32. Emil Adolf von Behring (1854 – 1917) • A Student of Koch • With Kitasato and Wernike, discovered anti-toxin • for Diphtheria and Tetanus and applied as therapy. • Awarded first Nobel Prize in physiology, 1901

33. Paul Ehrlich (1854 – 1915) Developed a series of tissue-staining dyes including that for tubercle bacillus. ·  Worked with Koch. Developed anti-toxin (Diphtheria) and hemalysis ·Side-chain theory of antibody formation: "surface receptors bound by lock & key; Ag stimulated receptors" ·   Shared 1908 Nobel Prize with Metchnikoff.

34. Elie Metchnikoff (1845-1916) ·   Embryologist studying starfish development. ·   Found phagocytosis. Phagocytes from larva stuck on thorn from a tangerine tree. Later he found a fungal spore attached to a phagocyte of Daphnia. Formed the basis of leukocyte phagocytosis. ·   Birth of cellular immunology Shared Nobel Prize with Ehrlich in 1908

35. Sir Frank Macfarlane Burnet (1899-1985) • ·    Trained as MD • ·    Important work on influenza. Discovery of an influenza viral enzyme with the specificity for particular forms of neuramic acid. Used today for detection. • Clonal selection theory to explain tolerance • 1960 Nobel Prize for the discovery of acquired immunological tolerance. Rejection of donor grafts was due to an immunological reaction and that tolerance can be built up by injections into embryos.

36. 1972 Nobel Prize for their discoveries concerning the chemical structure of antibodies. Rodney R. Porter 1917-1985 Gerald M. Edelman 1929-

37. BARUJ BENACERRAF JEAN DAUSSET GEORGE D. SNELL Discovered genes that regulate immune responses (Ir gene), Now known ad the major histocompatibility antigens 1980 Noble prize

38. Niels K. Jerne (1912-1994) ·   Antibody avidity maturation ·   Plaque forming assay ·   Pre-existing repertoire (in host DNA) theory helped the formation of clonal selection theory. ·   Host MHC is the driving force for the maturation and selection of T cells in the thymus. ·   **Idiotype network Nobel Prize, 1984, for theories concerning "the specificity in development and control of the immune system" and the discovery of "the principle for production of monoclonal antibodies."

39. Milstein (b. 1927) and Köhler (1946-1995) ·   Monoclonal antibody

40. Susumu Tonegawa (b. 1939) Cloning of the Immunoglobulin gene 1987 Nobel prize for his discovery of "the genetic principle for generation of antibody diversity".

41. Peter C. Doherty and Rolf M. Zinkernagel ·       Two signals ·        1996 Nobel Prize for their discoveries concerning "the specificity of the cell-mediated immune defence".

42. Timeline of immunology (wikipedia) • 1718 - Lady Mary Wortley Montagu, the wife of the British ambassador to Constantinople, observed the positive effects of variolation on the native population and had the technique performed on her own children. • 1798 - First demonstration of vaccination smallpoxvaccination (Edward Jenner) • 1837 - First description of the role of microbes in putrefaction and fermentation (Theodore Schwann) • 1838 - Confirmation of the role of yeast in fermentation of sugar to alcohol (Charles Cagniard-Latour) • 1840 - First "modern" proposal of the germ theory of disease (Jakob Henle) • 1850 - Demonstration of the contagious nature of puerperal fever (childbed fever) (Ignaz Semmelweis) • 1857-1870 - Confirmation of the role of microbes in fermentation (Louis Pasteur) • 1862 - phagocytosis (Ernst Haeckel) • 1867 - First aseptic practice in surgery using carbolic acid (Joseph Lister) • 1876 - First demonstration that microbes can cause disease-anthrax (Robert Koch) • 1877 - Mast cells (Paul Ehrlich) • 1878 - Confirmation and popularization of the germ theory of disease (Louis Pasteur) • 1880 - 1881 -Theory that bacterial virulence could be attenuated by culture in vitro and used as vaccines. Proposed that live attenuated microbes produced immunity by depleting host of vital trace nutrients. Used to make chicken cholera and anthrax "vaccines" (Louis Pasteur) • 1883 - 1905 - Cellular theory of immunity via phagocytosis by macrophages and microphages (polymorhonuclear leukocytes) (Elie Metchnikoff) • 1885 - Introduction of concept of a "therapeutic vaccination". First report of a live "attenuated" vaccine for rabies (Louis Pasteur). • 1888 - Identification of bacterial toxins (diphtheria bacillus) (Pierre Roux and Alexandre Yersin) • 1888 - Bactericidal action of blood (George Nuttall) • 1890 - Demonstration of antibody activity against diphtheria and tetanus toxins. Beginning of humoral theory of immunity. (Emil von Behring) and (Shibasaburo Kitasato) • 1891 - Demonstration of cutaneous (delayed type) hypersensitivity (Robert Koch) • 1893 - Use of live bacteria and bacterial lysates to treat tumors-"Coley's Toxins" (William B. Coley) • 1894 - Bacteriolysis (Richard Pfeiffer) • 1896 - An antibacterial, heat-labile serum component (complement) is described (Jules Bordet)

43. 1900 - Antibody formation theory (Paul Ehrlich) • 1901 - blood groups (Karl Landsteiner) • 1902 - Immediate hypersensitivity anaphylaxis (Paul Portier) and (Charles Richet) • 1903 - Intermediate hypersensitivity, the "Arthus reaction" (Maurice Arthus) • 1903 - Opsonization • 1905 - "Serum sickness" allergy (Clemens von Pirquet and (Bela Schick) • 1911 - 2nd demonstration of filterable agent that caused tumors (Peyton Rous) • 1917 - hapten (Karl Landsteiner) • 1921 - Cutaneous allergic reactions (Carl Prausnitz and Heinz Küstner) • 1924 - Reticuloendothelial system • 1938 - Antigen-Antibody binding hypothesis (John Marrack) • 1940 - Identification of the Rh antigens (Karl Landsteiner and Alexander Weiner) • 1942 - Anaphylaxis (Karl Landsteiner and Merill Chase) • 1942 - Adjuvants (Jules Freund and Katherine McDermott) • 1944 - hypothesis of allograft rejection • 1946 - identification of mouse MHC (H2) by George Snell and Peter A. Gorer • 1948 - antibody production in plasma B cells • 1949 - growth of polio virus in tissue culture, neutralization with immune sera, and demonstration of attenuation of neurovirulence with repetitive passage (John Enders) and (Thomas Weller) and (Frederick Robbins) • 1949 - immunological tolerance hypothesis • 1951 - vaccine against yellow fever • 1953 - Graft-versus-host disease • 1953 - immunological tolerance hypothesis • 1957 - Clonal selection theory (Frank Macfarlane Burnet) • 1957 - Discovery of interferon • 1958-1962 - Discovery of human leukocyte antigens (Jean Dausset and others) • 1959-1962 - Discovery of antibody structure (independently elucidated by Gerald Edelman and Rodney Porter) • 1959 - Discovery of lymphocyte circulation (James Gowans) • 1960 - Discovery of lymphocyte "blastogenic transformation" and proliferation in response to mitogenic lectins-phytohemagglutinin (PHA) (Peter Nowell)

44. 1961-1962 Discovery of thymus involvement in cellular immunity (Jacques Miller) • 1961- Demonstration that glucocorticoids inhibit PHA-induced lymphocyte proliferation (Peter Nowell) • 1963 - Development of the plaque assay for the enumeration of antibody-forming cells in vitro (Niels Jerne) (Albert Nordin) • 1964-1968 T and B cell cooperation in immune response • 1965 - Discovery of the first lymphocyte mitogenic activity, "blastogenic factor" (Shinpei Kamakura) and (Louis Lowenstein) (J. Gordon) and (L.D. MacLean) • 1965 - Discovery of "immune interferon" (gamma interferon) (E.F. Wheelock) • 1965 - Secretory immunoglobulins • 1967 - Identification of IgE as the reaginic antibody (Kimishige Ishizaka) • 1968 - Passenger leukocytes identified as significant immunogens in allograft rejection (William L. Elkins and Ronald D. Guttmann) • 1969 - The lymphocyte cytolysis Cr51 release assay (Theodore Brunner) and (Jean-Charles Cerottini) • 1971 - Peter Perlmann and Eva Engvall at Stockholm University invented ELISA • 1972 - Structure of the antibody molecule • 1974 - T-cell restriction to major histocompatibility complex (Rolf Zinkernagel and (Peter Doherty) • 1975 - Generation of the first monoclonal antibodies (Georges Köhler) and (César Milstein) • 1976 - Identification of somatic recombination of immunoglobulin genes (Susumu Tonegawa) • 1979 - Generation of the first monoclonal T cells (Kendall A. Smith) • 1980-1983 - Discovery and characterization of the first interleukins, 1 and 2 IL-1IL-2 (Kendall A. Smith) • 1981 - Discovery of the IL-2 receptor IL2R (Kendall A. Smith) • 1983 - Discovery of the T cell antigen receptor TCR (Ellis Reinherz) (Philippa Marrack) and (John Kappler) (James Allison) • 1983 - Discovery of HIV (Luc Montagnier) • 1984 - The first single cell analysis of lymphocyte proliferation (Doreen Cantrell) and (Kendall A. Smith) • 1985-1987 - Identification of genes for the T cell receptor • 1986 - Hepatitis B vaccine produced by genetic engineering • 1986 - Th1 vs Th2 model of T helper cell function (Timothy Mosmann) • 1988 - Discovery of biochemical initiators of T-cell activation: CD4- and CD8-p56lck complexes (Christopher E. Rudd) • 1990 - Gene therapy for SCID • 1994 - 'Danger' model of immunological tolerance (Polly Matzinger) • 1995 - Regulatory T cells (Shimon Sakaguchi) • 1996-1998 - Identification of Toll-like receptors • 2001 - Discovery of FOXP3 - the gene directing regulatory T cell development • 2005 - Development of human papillomavirus vaccine (Ian Frazer)

45. Looking back makes one know the path that leads to the future. A path is the foot prints of many, though only those walk in front are said heroes. When many walk together, a path comes into being.

46. Problem: Your friend made a big fortune in Atlantic City and asked you to help award any discovery ever made in the history of immunology. The recipient(s) could be dead or alive and the discovery could have or not have been awarded the Nobel prize. You have the great honor to nominate a candidate’s discovery. You are asked to provide a 3-page essay to support your nomination. Voluntary: Essay will not receive extra credit.