Timeline of immunology explained

The following are notable events in the Timeline of immunology:

• 1550 BCE – The Ebers papyrus recommends placing a poultice on a tumor and then making an incision, which would induce infection and cause regression of the tumor.^[1]
• 1549 – The earliest account of inoculation of smallpox (variolation) occurs in Wan Quan's (1499 - 1582) Douzhen Xinfa (痘疹心法).^[2]
• 1718 – Smallpox inoculation in Ottoman Empire realized by West, and Henry Kipkosgei, recorded the positive effects of variolation.
• 1761 – A case of breast cancer cured after ulcerating and getting infected is reported by Lambergen ^[3]
• 1796 – First demonstration of smallpox vaccination (Edward Jenner)
• 1808–1813 – First experimental demonstration of the germ theory of disease by Agostino Bassi though he does not formally propose the theory until 1844
• 1813 – Vautier reports spontaneous remission of cancer after gangrene infection (later to be known as Clostridium perfringens)
• 1829 – Another case of spontaneous remission of breast cancer after a patient refused surgery and the tumor ruptured, became infected and during a febrile illness with purulent discharge, it shrunk and disappeared after a few weeks. (Guillaume Dupuytren)^{[4] [5] [6]}
• 1837 – 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)
• 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 – Aseptic practice in surgery using carbolic acid (Joseph Lister)
• 1868 – Busch discovered that a sarcoma patient being surgically intervened to remove the tumor, after being exposed to a patient suffering from erysipelas, got a skin infection and her tumor disappeared. He inoculated some other cancer patients with many successes.^{[7] [4]}
• 1876 – 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 – 81 Theory that bacterial virulence could be attenuated by culture in vitro and used as vaccines. Used to make chicken cholera and anthrax "vaccines" (Louis Pasteur)
• 1882 – Identification of Streptococcus pyogenes as the causative agent of erysipelas (Friedrich Fehleisen). He repeats Busch experiments inoculating cancer patients with eryisipelas, noting tumor regression in many of them.^[8]
• 1883–1905 – Cellular theory of immunity via phagocytosis by macrophages and microphages (polymorhonuclear leukocytes) (Elie Metchnikoff)
• 1885 – Introduction of concept of a "therapeutic vaccination". Report of a live "attenuated" vaccine for rabies (Louis Pasteur and Pierre Paul Émile Roux).
• 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 (Kitasato Shibasaburō)
• 1891 – Demonstration of cutaneous (delayed type) hypersensitivity (Robert Koch)
• 1893 – Use of live bacteria and bacterial lysates to treat tumors – "Coley's Toxins", based on Busch and Fehleisen experiences (William B. Coley)
• 1894 – Bacteriolysis (Richard Pfeiffer)
• 1896 – An antibacterial, heat-labile serum component (complement) is described (Jules Bordet)
• 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^[9]
• 1905 – "Serum sickness" allergy (Clemens von Pirquet and (Bela Schick)
• 1909 – Paul Ehrlich proposes "immune surveillance" hypothesis of tumor recognition and eradication
• 1911 – 2nd demonstration of filterable agent that caused tumors (Peyton Rous)
• 1917 – Hapten (Karl Landsteiner)
• 1921 – Cutaneous allergic reactions (Otto 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
• 1945 – Coombs test antiglobulin test (AGT)
• 1946 – Identification of mouse MHC (H2) by George Snell and Peter A. Gorer
• 1948 – Antibody production in plasma B cells (Astrid Fagraeus)
• 1949 – Growth of polio virus in tissue culture, neutralization, and demonstration of attenuation of neurovirulence (John Enders) and (Thomas Weller) and (Frederick Robbins)
• 1951 – A vaccine against yellow fever
• 1953 – Graft-versus-host disease
• 1953 – Validation of immunological tolerance hypothesis
• 1957 – Clonal selection theory (Frank Macfarlane Burnet)
• 1957 – Discovery of interferon by Alick Isaacs and Jean Lindenmann^[10]
• 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)
• 1961–1962 Discovery of thymus involvement in cellular immunity (Jacques Miller)
• 1960 – Radioimmunoassay – (Rosalyn Sussman Yalow)
• 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 by Niels Jerne and Albert Nordin
• 1963 – Gell and Coombs classification of hypersensitivity
• 1964–1968 – T and B cell cooperation in immune response
• 1965 – Discovery of 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
• 1972 – Discovery of invertebrate immunity by Hans G. Boman^[11]
• 1973 – Dendritic Cells first described by Ralph M. Steinman
• 1974 – Immune Network Hypothesis (Niels Jerne)
• 1974 – T-cell restriction to MHC (Rolf Zinkernagel and (Peter C. Doherty)
• 1975 – Generation of monoclonal antibodies (Georges Köhler) and (César Milstein)^[12]
• 1975 – Discovery of Natural Killer cells (Rolf Kiessling, Eva Klein, Hans Wigzell)
• 1976 – Identification of somatic recombination of immunoglobulin genes (Susumu Tonegawa)
• 1980–1983 – Discovery and characterization of interleukins, 1 and 2 IL-1 IL-2 (Robert Gallo, Kendall A. Smith, Tadatsugu Taniguchi)
• 1981 – First description of an animal antimicrobial peptide in Cecropia silk moths^[13]
• 1983 – Discovery of the T cell antigen receptor TCR (Ellis Reinherz) (Philippa Marrack) and (John Kappler)^[14] (James Allison)
• 1983 – Discovery of HIV (Luc Montagnier) (Françoise Barré-Sinoussi) (Robert Gallo)
• 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
• 1991 – Role of peptide for MHC Class II structure (Scheherazade Sadegh-Nasseri & Ronald N. Germain)^[15]
• 1992 – Discovery of transitional B cells (David Allman & Michael Cancro)^{[16] [17]}
• 1994 – Danger model of immunological tolerance is described by Polly Matzinger at the NIH
• 1995 – James P. Allison is the first to describe the function of the critical immune checkpoint CTLA-4
• 1995 – Regulatory T cells (Shimon Sakaguchi)
• 1995 – First Dendritic cell vaccine trial reported by Mukherji et al.
• 1995 – Discovery of the insect Imd NF-κB pathway^[18]
• 1996–1998 – Identification of Toll-like receptors as immune-regulating molecules^[19]
• 1997 – Discovery of the autoimmune regulator and the AIRE gene.
• 2000 – Characterization of M1 and M2 macrophage subsets by Charles Mills^[20]
• 2001 – Discovery of FOXP3 – the gene directing regulatory T cell development
• 2005 – Development of human papillomavirus vaccine (Ian Frazer)
• 2006 – Antigen-specific NK cell memory first reported by Ulrich von Andrian's group after discovery by Mahmoud Goodarzi
• 2010 – The first autologous cell-based cancer vaccine, Provenge, is approved by the FDA for the treatment of metastatic, asymptomatic stage IV prostate cancer.
• 2010 – First immune checkpoint inhibitor, ipilimumab (anti-CTLA-4), is approved by the FDA for treatment of stage IV melanoma
• 2011 – Carl H. June reports first successful use of CAR T-cells expressing the 4-1BB costimulatory signaling domain for the treatment of CD19+ malignancies
• 2014 – A second class of immune checkpoint inhibitor (anti-PD-1) is approved by the FDA for the treatment of melanoma. Pembrolizumab and nivolumab are approved within months of each other.
• 2016 – The role of dendritic cell expressed CTLA-4 in Th immune polarization is first described
• 2016 – A third class of immune checkpoint inhibitor, anti-PD-L1 (atezolizumab), is approved for the treatment of bladder cancer
• 2017 – First autologous CAR T-cell therapy tisagenlecleucel approved for the treatment of pediatric B-ALL; second autologous CAR T-cell therapy axicabtagene ciloleucel (Yescarta) is approved.
• 2020 – The first mRNA vaccines (BNT162b2, mRNA-1273), are developed for SARS-CoV-2 infection; this new technology completed design, testing, and emergency approval in under one year.

Notes and References

1. Jessy T . Immunity over inability: The spontaneous regression of cancer . Journal of Natural Science, Biology, and Medicine . 2 . 1 . 43–49 . January 2011 . 22470233 . 3312698 . 10.4103/0976-9668.82318 . free .
2. Needham, Joseph. (2000). Science and Civilization in China: Volume 6, Biology and Biological Technology, Part 6, Medicine . Cambridge: Cambridge University Press. Page 134.
3. Web site: Recherches sur le traitement médical des tumeurs cancéreuses du sein: Ouvrage pratique basé sur trois cents observations (Extraites d'un grand nombre d'auteurs) avec des planches et une statistique sur la fréquence de ces maladies . Tanchou S . 1844 .
4. Kucerova P, Cervinkova M . Spontaneous regression of tumour and the role of microbial infection--possibilities for cancer treatment . Anti-Cancer Drugs . 27 . 4 . 269–277 . April 2016 . 26813865 . 4777220 . 10.1097/CAD.0000000000000337 .
5. Hoption Cann SA, van Netten JP, van Netten C . Acute infections as a means of cancer prevention: opposing effects to chronic infections? . Cancer Detection and Prevention . 30 . 1 . 83–93 . 1 January 2006 . 16490323 . 10.1016/j.cdp.2005.11.001 .
6. Dupuytren G . De la gangrène spontanée générale et partielle des tumeurs cancéreuses du sein. . J Hebdom Med . 4.
7. Web site: Busch W . Berliner klinische Wochenschrift.1868 (137) . 1864 . 58 v .
8. Wei MQ, Mengesha A, Good D, Anné J . Bacterial targeted tumour therapy-dawn of a new era . Cancer Letters . 259 . 1 . 16–27 . January 2008 . 18063294 . 10.1016/j.canlet.2007.10.034 .
9. Wright AE, Stewart RD . An experimental investigation on the role of the blood fluids in connection with phagocytosis. Proceedings of the Royal Society of London. 1 September 1903. 72. 477–486. 357–370. 10.1098/rspl.1903.0062. free.
10. News: Gina . Kolata . Jean Lindenmann, Who Made Interferon His Life's Work, Is Dead at 90 . . 22 January 2015 . 12 February 2015 . 27 December 2019 . https://web.archive.org/web/20191227123436/https://www.nytimes.com/2015/01/23/us/jean-lindenmann-made-interferon-his-lifes-work-is-dead-at-90.html?_r=0 . live .
11. Boman HG, Nilsson I, Rasmuson B . Inducible antibacterial defence system in Drosophila . Nature . 237 . 5352 . 232–235 . May 1972 . 4625204 . 10.1038/237232a0 . 1972Natur.237..232B . 4277142 .
12. Köhler G, Milstein C . Continuous cultures of fused cells secreting antibody of predefined specificity . Nature . 256 . 5517 . 495–497 . August 1975 . 1172191 . 10.1038/256495a0 . 4161444 . 1975Natur.256..495K .
13. Steiner H, Hultmark D, Engström A, Bennich H, Boman HG . Sequence and specificity of two antibacterial proteins involved in insect immunity . Nature . 292 . 5820 . 246–248 . July 1981 . 7019715 . 10.1038/292246a0 . 1981Natur.292..246S . 4269791 .
14. Haskins K, Kubo R, White J, Pigeon M, Kappler J, Marrack P . The major histocompatibility complex-restricted antigen receptor on T cells. I. Isolation with a monoclonal antibody . The Journal of Experimental Medicine . 157 . 4 . 1149–1169 . April 1983 . 6601175 . 2186983 . 10.1084/jem.157.4.1149 .
15. Sadegh-Nasseri S, Germain RN . A role for peptide in determining MHC class II structure . Nature . 353 . 6340 . 167–170 . September 1991 . 1653903 . 10.1038/353167a0 . 4363105 . 1991Natur.353..167S .
16. Allman DM, Ferguson SE, Cancro MP . Peripheral B cell maturation. I. Immature peripheral B cells in adults are heat-stable antigenhi and exhibit unique signaling characteristics . Journal of Immunology . 149 . 8 . 2533–2540 . October 1992 . 1383316 . 10.4049/jimmunol.149.8.2533 . 38398038 . free .
17. Allman DM, Ferguson SE, Lentz VM, Cancro MP . Peripheral B cell maturation. II. Heat-stable antigen(hi) splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells . Journal of Immunology . 151 . 9 . 4431–4444 . November 1993 . 8409411 . 10.4049/jimmunol.151.9.4431 . 1805107 . free .
18. Lemaitre B, Kromer-Metzger E, Michaut L, Nicolas E, Meister M, Georgel P, Reichhart JM, Hoffmann JA . 6 . A recessive mutation, immune deficiency (imd), defines two distinct control pathways in the Drosophila host defense . Proceedings of the National Academy of Sciences of the United States of America . 92 . 21 . 9465–9469 . October 1995 . 7568155 . 40822 . 10.1073/pnas.92.21.9465 . 1995PNAS...92.9465L . free .
19. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA . The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults . Cell . 86 . 6 . 973–983 . September 1996 . 8808632 . 10.1016/s0092-8674(00)80172-5 . 10736743 . free .
20. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM . M-1/M-2 macrophages and the Th1/Th2 paradigm . Journal of Immunology . 164 . 12 . 6166–6173 . June 2000 . 10843666 . 10.4049/jimmunol.164.12.6166 . free .