Prepared By:V.Madhukar

Nobel Discoveries in Immunology

1901- Till Date

The Nobel Prize is a set of annual international awards bestowed in a number of categories by Swedish and Norwegian committees in recognition of academic, cultural and/or scientific advances. The will of the Swedish inventor Alfred Nobel established the prizes in 1895.

The prizes in Physics, Chemistry, Physiology or Medicine, Literature, and Peace were first awarded in 1901

Nobel Prize

Name(Age) Year

Location

Field of Work

Emil von Behring (60)

1901

Germany

Diptheria Antitoxin

Paul Ehrlich(54)

1908

Germany

Adaptive Immunity, Autoimmunity

Ilya Mechnikov(63)

1908

France Phagocytosis and The macrophage

Jules Bordet(49)

1919

Belgium Complement system in Immune system

Karl Landsteiner(62)

1930

Vienna Human Blood Types Discovery

Macfarlane Burnet(61)

1960

Australia

Theory Of Immune Tolerance

Peter Medawar(45)

1960

UK Experiments On Immune Tolerance

Gerald Edelman(43)

1972

USA Chemical Structure of Immunoglobulin

Rodney Porter(55)

1972

UK Chemical Structure of Immunoglobulin

Nobel Laureates In Immunology

Jean Dausset(64)

1980

France Human MHC

George Snell(77)

1980

USA Mouse MHC

Baruj Benacerraf(60)

1980

USA MHC Immune-Response Genes

Niels Jerne(73) 1984

Switzerland

Theory of Immunity

Cesar Milstein(57)

1984

UK Monoclonal Antibodies

Georges Kohler(38)

1984

Switzerland

Monoclonal Antibodies

Rolf Zinkernagel(52)

1996

Switzerland

CMI and MHC Restriction

Peter Doherty(56)

1996

Australia Cellular Immune Defense

Bruce Beutler(54)

2011

USA Activation of Innate Immunity

Jules Hoffmann(70)

2011

France Activation of Innate Immunity

Ralph Steinman(67)

2011

Canada Dendritic Cell and its Role in Adaptive Immunity

Contd.

Behring and Kitasato jointly published their classic paper, "Ueber das Zustandekommen der Diphtherie-Immunität und der Tetanus-Immunität bei Thieren" ("The Mechanism of Immunity in Animals to Diphtheria and Tetanus"). One week later, Behring alone published another paper dealing with immunity against diphtheria and outlining five ways in which it could be achieved. These reports announced that injections of toxin from diphtheria or tetanus bacilli led animals to produce in their blood substances capable of neutralizing the disease poison.Behring and Kitasato dubbed these substances ANTITOXINS. Furthermore, injections of blood serum from an animal that had been given a chance to develop antitoxins to tetanus or diphtheria could confer immunity to the disease on other animals, and even cure animals that were already sick.

Emil Von Behring (1901)Prize motivation: "for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths”

Ehrlich, then a relatively obscure German scientist, had been awarded the Nobel Prize in Medicine. He shared the honor with the much more famous but now almost forgotten Ilya Mechnikov for their work on Immunity. Paul Ehrlich :Paul Ehrlich worked with Robert Koch on serum research and then also worked with Emil Behring on Diptheria. He is well known for works in autoimmunity and adaptive immunity. Ehrlich after working with Koch and Behring  devoted himself to chemotherapy. His aim was, as he put it, to find chemical substances which have special affinities for pathogenic organisms, to which they would go, as antitoxins go to the toxins to which they are specifically related, and would be, as Ehrlich expressed it, «magic bullets» which would go straight to the organisms at which they were aimed.

Paul Ehrlich and Ilya Mechnikov (1908)Prize motivation: “in recognition of their work on immunity”

Ehrlich had, like so many other discoverers before him, to battle with much opposition before Salvarsan or Neosalvarsan (more than 900 tests were performed) were accepted for the treatment of human syphilis; but ultimately the practical experience prevailed and Ehrlich became famous as one of the main founders of chemotherapy.

Ilya Mechnikov It was at Messina in a private laboratory that he discovered the phenomenon of phagocytosis with which his name will always be associated. This discovery was made when Mechnikov observed, in the larvae of starfishes, mobile cells which might, he thought, serve as part of the defenses of these organisms and, to test this idea, he introduced into them small thorns from a tangerine tree which had been prepared as a Christmas tree for his children. Next morning he found the thorns surrounded by the mobile cells, and, knowing that, when inflammation occurs in animals which have a blood vascular system, leucocytes escape from their blood vessels, it occurred to him that these leucocytes might take up and digest bacteria that get into the body.

Mechnikov Ehrlich and Hata

His discovery that the bacteriolytic effect of acquired specific antibody is significantly enhanced in vivo by the presence of innate serum components which he termed alexine (but which are now known as complement). This mechanism became the basis for complement-fixation testing methods that enabled the development of serological tests for syphilis. The same technique is used today in serologic testing for countless other diseases.Together with Gengou (in 1906), he cultivated B.pertussis and laid the foundations of the generally accepted opinion that this organism is the bacterial cause of whooping cough. In addition to his being an acknowledged world authority in many branches of bacteriology, Bordet was considered to be a great exponent and worker on immunology.

Jules Bordet (1919)Prize motivation: “for his discoveries relating to immunity”

Jules Bordet

After leaving school, Landsteiner studied medicine at the University of Vienna, graduating in 1891. Even while he was a student he had begun to do biochemical research and in 1891 he published a paper on the influence of diet on the composition of blood ash.In 1875 Landois had reported that, when man is given transfusions of the blood of other animals, these foreign blood corpuscles are clumped and broken up in the blood vessels of man with the liberation of haemoglobin. In 1901-1903 Landsteiner pointed out that a similar reaction may occur when the blood of one human individual is transfused, not with the blood of another animal, but with that of another human being, and that this might be the cause of shock, jaundice, and haemoglobinuria that had followed some earlier attempts at blood transfusions.

Karl Landsteiner(1930)Prize motivation: “for his discovery of human blood groups”

His suggestions, however, received little attention until, in 1909, he classified the bloods of human beings into the now well-known A, B, AB, and O groups and showed that transfusions between individuals of groups A or B do not result in the destruction of new blood cells and that this catastrophe occurs only when a person is transfused with the blood of a person belonging to a different group. Earlier, in 1901-1903, Landsteiner had suggested that, because the characteristics which determine the blood groups are inherited, the blood groups may be used to decide instances of doubtful paternity.

To the end of his life, Landsteiner continued to investigate blood groups and the chemistry of antigens, antibodies and other immunological factors that occur in the blood. It was one of his great merits that he introduced chemistry into the service of serology.

Karl Landsteiner

Using the concept of self, Burnet introduced a hypothesis about the situation where the body failed to make antibodies to its own components (autoimmunity) and by extension the idea of immune tolerance. He proposed thatif in embryonic life expendable cells from a genetically distinct race are implanted and established, no antibody response should develop against the foreign cell antigen when the animal takes on independent existenceBurnet was, however, unable to prove this experimentally. Peter Medawar, Rupert E. Billingham and Leslie Brent did find support for Burnet's hypothesis in 1953 when they showed that splenocytes could be engrafted by intravenous infusion into mice in utero or just after birth and that when these mice matured, they could accept skin and other tissues from the donor but not from any other mouse strain. Burnet and Medawar were co-recipients of the 1960 Nobel Prize in Physiology or Medicine for this work, as it provided the experimental basis for inducing immune tolerance, thereby allowing the transplantation of solid organs. 

Macfarlane Burnet and Peter Medawar (1960)Awarded jointly to Sir Frank Macfarlane Burnet and Peter Brian Medawar  "for discovery of acquired immunological tolerance”

Sir Frank Macfarlane Peter MedawarBurnet

Responding to external threats such as disease-causing microorganisms, protein antibody molecules are released by specialized immune cells into the blood stream to disarm the threat. Their mode of attack is target recognition: millions of different molecules can be created, each with a different binding site, which can identify distinctive proteins on their specifically assigned foe with pinpoint accuracy.A long-standing question in the field was how an almost identical-looking collection of antibody proteins can, at the same time, have the capacity to target specifically any one of an almost infinite range of foreign agents.

Gerald Edelman and Rodney Porter(1972)Prize motivation: “for their discoveries in concerning the chemical structure of antibodies”

Gerald Edelman and Rodney Porter independently took similar approaches to deciphering their structure, both realizing that the best way in which to grasp the finer aspects of such large molecules was to split them into smaller, more manageable pieces. Their deconstruction methods differed. Porter used a protein-cleaving enzyme that fragmented an antibody molecule into its functional subsections. Edelman's approach destroyed antibody function by using chemicals to break the bridge-like bonds that keep the constituent protein chains together, his procedure relying on the finding that copious quantities of antibodies are produced by cancerous versions of white blood cells.

Gerald Edelman Rodney Porter

While fighting off infectious agents, our immune defences must take extreme care not to avoid harming any cells belonging to its own host. Achieving this requires a sophisticated self-identification system, and this is centred on a collection of genes called the major histocompatibility complex, or MHC, which encode proteins known collectively as histocompatibility antigens. Each individual carries a unique combination of these antigens on the surface of their cells, providing a form of biological ID system for distinguishing one individual from another.

Baruj Benacerraf, George Snell and Jean Dausset (1980)Prize motivation: “for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions”

George Snell discovered the first components of the MHC in the 1940s through their role in rejecting transplants in mice. At that time, the search for genetic factors that reject tumour transplants had been narrowed down to a number of possible locations on mouse chromosomes .On closer inspection, what appeared to be a single gene in the neighbourhood turned out to be a surprisingly large number of genes that were closely linked together.Around a decade later, Jean Dausset uncovered the first compatibility antigen in humans. He noticed that a patient receiving several transfusions of ABO compatible blood still suffered an unexpected immune reaction. Dausset discovered that in this case antibodies were being launched against white blood cells belonging to the donor only, and that these antibodies in the patient’s serum triggered a similar reaction in half the samples of white blood cells taken from other people. He called the factor responsible MAC, and this turned out to be the first of a series of human leukocyte antigens, or HLAs.

Experiments by Baruj Benacerraf in the 1970s provided the first indication that immune reactions are controlled by genes. Benacerraf was surprised to discover that different strains of guinea pigs launched different levels of attack towards the same foreign antigen, and he traced the cause to what he termed immune response genes.

Baruj Benacerraf George Snell Jean Dausset

The important contribution of theory and practice in shaping our understanding of the body's immune system. The hypotheses formulated by Niels Jerne presented a clearer image of the way in which a diverse range of antibodies can be engaged to fight an invader. Georges Köhler and César Milstein constructed perpetual antibody-production lines that have become an essential laboratory tool for researchers worldwide.Milstein had developed cancerous forms of antibody-producing cells that grew and multiplied forever, but which churned out antibodies of unknown specificity; while Köhler had tweaked normal antibody-producing cells to produce specific antibodies, but they survived for a few days only in culture.

Niels Jerne, Cesar Milstein and Georges Kohler(1984)Prize Motivation: “for theories concerning the specificity in development and control of the immune system and the discovery of the principle

for production of monoclonal antibodies”

Combining forces, the neat trick they came up with was to fuse a normal antibody-producing cell with a tumour cell, forming a hybrid that was both immortal and could create a specific antibody. Köhler and Milstein's technique for creating any single predetermined type of so-called monoclonal antibody on demand has led to many medicine and biomedical applications, from creating more reliable probes for blood and tissue typing tests, to designing completely new therapeutic strategies for diseases such as cancer.

Niels Jerne Cesar Milstein Georges Kohler

Viruses, such as those that cause the common cold or flu, are a particularly devious form of intruder to tackle. Once they enter their host, these infectious agents find cells to hide in while they reproduce in order to infiltrate more targets. Fortunately for us our internal defence system has a trick up its sleeve to seek out this hidden threat. It recruits a specialized form of white blood cell, T killer lymphocytes, that can identify and destroy virus-infected cells, and yet can somehow leave normal healthy cells unharmed.

Peter Doherty and Rolf Zinkernagel(1996)Prize Motivation : “for their discoveries concerning the specificity of the cell mediated immune defence"

 Investigating how mice are protected against infection from a viral agent that can cause the disease meningitis, they were surprised to find that virus-killing T lymphocytes taken from a mouse could only execute their destructive effect in infected cells belonging to the same strain. Doherty and Zinkernagel proposed that lymphocytes ignored infected cells in other strains because they need to simultaneously recognize two distinct signals on their suspected target – a specific molecule belonging to the concealed virus, and a specific protein marker found on all host cells that signifies that it belongs to itself. Closer inspection revealed that the virus' molecule actually distorts the host's marker protein by attaching to it, and this altered self protein informs the T lymphocytes that the cell is infected.Doherty and Zinkernagel's findings finally unmasked the true purpose of these self-recognition protein molecules, the major histocompatibility antigens. Why these proteins create a barrier to transplantation was far from obvious, but the discoveries of Doherty and Zinkernagel revealed that this is merely an unavoidable side-effect of their true biological function. Acting as a surveillance system to distinguish self from non-self, these major histocompatibility antigens allow immune cells to make their crucial life-or-death decision in the face of numerous threats.

Peter Doherty Rolf Zinkernagel

The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity" The other half to Ralph M. Steinman "for his discovery of the dendritic cell and its role in adaptive immunity".Ralph Steinman : Steinman’s early research in collaboration with Cohn was an attempt to understand the white cells of the immune system that operate in a variety of ways to spot, apprehend, and destroy infectious microorganisms and tumor cells. In 1973, Steinman and Cohn discovered dendritic cells, a previously unknown class of immune cells that constantly formed and retracted their processes. This discovery changed the field of immunology.

Bruce Beutler, Jules Hoffmann and Ralph Steinman (2011)

For the next four decades, until his death in 2011, Steinman’s laboratory was at the forefront of dendritic cell research. He and his colleagues established that dendritic cells are critical sentinels of the immune system that control both its innate and adaptive responses - from silencing to actively resisting its challenges. He also showed that dendritic cells are the 2 main initiators of T cell-mediated immune responses.His most recent studies were focused on the interface of several diseases with the immune system and included clinical studies using dendritic cell- and immune-based vaccines and therapies for such medical conditions as graft rejection, resistance to tumors, autoimmune diseases, and infections. In 2010, he initiated at The Rockefeller University Hospital a phase I clinical trial with the first dendritic cell-targeted vaccine against HIV.Diagnosed with pancreatic adenocarcinoma in March 2007, Steinman believed that dendritic cells had the potential to fight his aggressive tumor. With many collaborators and leading-edge technology, he designed dendritic cell-based immunotherapies for himself that he thought might also advance medical science. 

Bruce Beutler and Jules Hoffmann :Beutler and Hoffman helped to elucidate innate immunity. That’s the non-specific array of initial responses by the body’s immune system that can recognize invading microorganisms as being foreign and try to destroy them.Dr.Hoffman found in fruit flies, and Dr.Beutler subsequently discovered in mice, a crucial protein-binding mechanism that helps the immune system recognize invaders and trigger an immune response against them.

Together, these discoveries made it possible to develop new vaccines to fight infections and to encourage the immune system to attack tumors.

Bruce Beutler Jules Hoffmann Ralph Steinman

Oxford Kuby J(1997) Immunology- WH Freeman and Company

Ivan M Roit(1994) Essential Immunology- Blackwell Scientific Publications

Links:www.nobelprize.orgwww.nature.com (Nature Immunology)

References

“What I have achieved is a single stone from the beach of Knowledge, There is more to explore!”

- Albert Einstein

THANK YOU! And Lets Explore. . .