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Discovering
cells of the immune system
With the advantage of hindsight we know that this still leaves
a big hole in the understanding of our immune system. Antibody
production is only one part of the response against a pathogenic
challenge. What of the cellular immune system? With such significant
advances in understanding antibodies there were few supporters
of a cellular defense system at the turn of the century. However
the were a few scientists who resisted the majority held humoral
view of the immune system.
The idea of cells being directly involved in the defense of
the body was first suggested by Ilya Metchnikoff in 1884. Metchnikoff
was a zoologist who had studied single cell organisms and phagocytes
in transparent starfish larvae. He was well aware that single
cell organisms took in food by phagocytosis and released debris
by exocytosis. Metchnikoff suggested that phagocytic cells in
vertebrates would operate in a similar way to remove microorganisms.
His famous experiment involved simply pushing a rose thorn into
starfish larva and observing that phagocytic cells rapidly migrated
and clustered around the thorn.
The defense and challenge to the idea of phagocytes operating
in the immune defense system was a long drawn out affair. By 1901,
when Metchnikoff published his extensive book supporting phagocytic
immunity, the humoralists had all but won the day. The cellular
theory for the immune system had to wait until the 1940s for a
revival of interest and ultimate discovery.
Contact
sensitivity and dermatitis
Koch in his work on tuberculosis had observed that when the bacteria
was inhaled and settled in the lungs it caused the formation of
tissue nodules which eventually became necrotic. He also noticed
that when he transferred the bacteria from one animal to another
the inoculation site also became necrotic. The "Koch phenomenon"
later became known as "delayed type hypersensitivity".
Understanding hypersensitivity would be the key to recognition of
a cellular immune system.
At the start of the 20 century physicians were well aware of the
bodies ability to develop a reaction consisting of a rash, itching
and oozing from vesicular lesions in response to compounds such
as mercury, poison ivy and certain cosmetics. This response was
known as contact sensitivity or contact dermatitis. It was clear
that in contact sensitivity the first exposure to a compound produced
a slow reaction but subsequent exposure resulted in a much faster
response and swift development of symptoms.
Originally it was believed the reaction was mediated by antibodies.
On this assumption Karl Landsteiner and friends began his investigation
into contact sensitivity. They took the standard approach used to
transfer antibodies from an affected animal to an unaffected one
(in other words they wanted to transfer passive immunity). They
sensitized an animal and then took serum from it and injected the
serum into an untreated animal. They then applied the sensitizing
compound to this animal. However, they found that transfer of serum
did not help improve the sensitivity response.
For reasons unknown, Landsteiner and friends decided they would
isolate white blood cells from the blood and transfer these. Lucky
for them the recipient animal must have been related to the donor
(if not the recipient's immune system would have quickly gone to
work to kill off the injected cells). They found that the recipient
became as sensitive as the donor animal. Landsteiner and friends
then switched to looking at the delayed type hypersensitivity reaction
in tuberculosis. In similar fashion they demonstrated that transferring
cells from an affected animal into an unaffected one conferred a
sensitivity response to tuberculosis. This work, demonstrating white
blood cells were involved in contact sensitivity and delayed type
hypersensitivity was published in 1942 but it failed to grab the
attention of most immunologists who were still convinced that antibodies
were the main mechanism of disease resistance.
The recognition of inflammatory cells being involved in rejection
of grafts had been known for some time but it was Peter Medawar
and Thomas Gibson's work in this area that brought real interest.
Medawar and Gibson had an incentive working in their favor, the
second world war. The war spurred interest in the area of skin grafting
for wounds and burns patients. From 1944 onwards a whole series
of papers were published by these two on graft rejection and how
it was mediated by immune cells. The shear volume of work that was
published made the idea of cell mediated graft rejection impossible
to object to. Medawar's work demonstrated the stages of cellular
infiltration into skin grafts and rapid destruction of the graft.
It took more work in areas of immunodeficiency and autoimmunity
before the idea of cell mediated immunity was completely accepted
but we shall look at these areas later. Cellular immunology came
into its own in the 1950s and today probably holds dominance of
interest for most immunologists.
Conclusions
From reading this you may think that immunology developed in a
systematic and chronological order. Of course it did not. Development
of an understanding was slow with leads down many blind alleys before
finding the right path. Arguments between the different schools
of thought on the immune system were (still are!) very bitter. Many
of the developments were accidental and took a long time to be developed
into established principles. We could continue with our exploration
of the history of immunology but I think we now have the basics
in place to move on. We have recognised the development of modern
western science and its roots in middle and far east medicine. We
have looked at the development of the possibility that the body
has a defense system against infection that can be boosted and accentuated
by vaccines in the fight against infection, and we have recorded
how we developed and understanding of the humoral and cellular arms
of the immune system. Now let's take a look at development of the
immune system from nature's historical perspective.
History
of immunology time line
- 1798 Edward Jenner, Smallpox vaccination
- 1862 Ernst Haeckel, Recognition of phagocytosis
- 1877 Paul Erlich, recognition of mast cells
- 1879 Louis Pasteur, Attenuated chicken cholera vaccine development
- 1883 Elie Metchnikoff Cellular theory of vaccination
- 1885 Louis Pasteur, Rabies vaccination development
- 1888 Pierre Roux & Alexandre Yersin, Bacterial toxins
- 1888 George Nuttall, Bactericidal action of blood
- 1891 Robert Koch, Delayed type hypersensitivity
- 1894 Richard Pfeiffer, Bacteriolysis
- 1895 Jules Bordet, Complement and antibody activity in bacteriolysis
- 1900 Paul Erlich, Antibody formation theory
- 1901 Karl Landsteiner, A, B and O blood groupings
- 1901-8 Carl Jensen & Leo Loeb, Transplantable tumors
- 1902 Paul Portier & Charles Richet, Anaphylaxis
- 1903 Almroth Wright & Stewart Douglas, Opsonization reactions
- 1906 Clemens von Pirquet, coined the word allergy
- 1907 Svante Arrhenius, coined the term immunochemistry
- 1910 Emil von Dungern, & Ludwik Hirszfeld, Inheritance of ABO
blood groups
- 1910 Peyton Rous, Viral immunology theory
- 1914 Clarence Little, Genetics theory of tumor transplantation
- 1915-20 Leonell Strong & Clarence Little, Inbred mouse strains
- 1917 Karl Landsteiner, Haptens
- 1921 Carl Prausnitz & Heinz Kustner, Cutaneous reactions
- 1924 L Aschoff, Reticuloendothelial system
- 1926 Lloyd Felton & GH Bailey, Isolation of pure antibody preparation
- 1934-8 John Marrack, Antigen-antibody binding hypothesis
- 1936 Peter Gorer, Identification of the H-2 antigen in mice
- 1940 Karl Lansteiner & Alexander Weiner, Identification of the
Rh antigens
- 1941 Albert Coons, Immunofluorescence technique
- 1942 Jules Freund & Katherine McDermott, Adjuvants
- 1942 Karl Landsteiner & Merill Chase, Cellular transfer of sensitivity
in guinea pigs (anaphylaxis)
- 1944 Peter Medwar, Immunological hypothesis of allograft rejection
- 1948 Astrid Fagraeus, Demonstration of antibody production in
plasma B cells
- 1948 George Snell, Congenic mouse lines
- 1949 Macfarlane Burnet & Frank Fenner, Immunological tolerance
hypothesis
- 1950 Richard Gershon and K Kondo, Discovery of suppressor T
cells
- 1952 Ogden and Bruton, discovery of agammagobulinemia (antibody
immunodeficiency)
- 1953 Morton Simonsen and WJ Dempster, Graft-versus-host reaction
- 1953 James Riley & Geoffrey West, Discovery of histamine in
mast cells
- 1953 Rupert Billingham, Leslie Brent, Peter Medwar, & Milan
Hasek, Immunological tolerance hypothesis
- 1955-1959 Niels Jerne, David Talmage, Macfarlane Burnet, Clonal
selection theory
- 1957 Ernest Witebsky et al., Induction of autoimmunity in animals
- 1957 Alick Isaacs & Jean Lindemann, Discovery of interferon
(cytokine)
- 1958-62 Jean Dausset et al., Human leukocyte antigens
- 1959-62 Rodney Porter et al., Discovery of antibody structure
- 1959 James Gowans, Lymphocyte circulation
- 1961-62 Jaques Miller et al., Discovery of thymus involvement
in cellular immunity
- 1961-62 Noel Warner et al., Distinction of cellular and humoral
immune responses
- 1963 Jaques Oudin et al., antibody idiotypes
- 1964-8 Anthony Davis et al., T and B cell cooperation in immune
response
- 1965 Thomas Tomasi et al., Secretory immunoglobulin antibodies
- 1967 Kimishige Ishizaka et al., Identification of IgE as the
reaginic antibody
- 1971 Donald Bailey, Recombinent inbred mouse strains
- 1974 Rolf Zinkernagel & Peter Doherty, MHC restriction
- 1975 Kohler and Milstein, Monoclonal antibodies used in genetic
analysis
- 1984 Robert Good, Failed treatment of severe combined immunodeficiency
(SCID, David the bubble boy) by bone marrow grafting.
- 1985 Tonegawa, Hood et al., Identification of immunoglobulin
genes
- 1985-7 Leroy Hood et al., Identification of genes for the T
cell receptor
- 1990 Yamamoto et al., Molecular differences between the genes
for blood groups O and A and between those for A and B
- 1990 NIH team, Gene therapy for SCID using cultured T cells.
- 1993 NIH team, Treatment of SCID using genetically altered umbilical
cord cells.
- 1985-onwards Rapid identification of genes for immune cells,
antibodies, cytokines and other immunological structures.
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