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Para
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Microb

P ETE R AR
M ED A W

FATHER OF
TRANSPLANTATION
SIR PETER MEDAWAR MADE SIGNIFICANT CONTRIBUTIONS TO
IMMUNOLOGY, PARTICULARLY IN ACQUIRED IMMUNE TOLERANCE

Skin Grafting Studies (1940s-1950s)

- Medawar's experiments on skin grafting in mice
revealed the phenomenon of immunological
tolerance. He found that repeated exposure to skin
grafts from the same donor led to the acceptance
of subsequent grafts, indicating the development
of acquired tolerance.
Richard Dawkins referred to him as "the wittiest
of all scientific writers"
Stephen Jay Gould as "the cleverest man I have
ever known".

Immunological Privilege (1948) Nobel Prize in Physiology or Medicine

- Medawar introduced the concept of immunological Peter Medawar was awarded jointly with Sir Macfarlane Burnet (AAI
privilege, describing certain tissues as being protected '61) for their "discovery of acquired immunological tolerance."
from immune responses. This idea contributed to our Medawar provided experimental evidence that confirmed Burnet's
understanding of how the immune system interacts with theory of immunological tolerance, which hypothesized that the
different tissues and organs, influencing the concept of "self" was defined by the immune system during
development of tolerance. embryogenesis.

Burnet-Medawar Hypothesis (1953) The discovery of acquired immunological tolerance

- Medawar, along with Sir Frank Macfarlane Burnet,
proposed the clonal selection theory, which
explained how the immune system recognizes and
responds to specific antigens. This laid the
foundation for understanding acquired immune
tolerance.
SAcquired Tolerance in Twins (1953):
- Medawar's work on fraternal twin cattle
demonstrated that when one twin is exposed to
tissues from the other in early development, immune
tolerance is induced. This provided crucial insights
into the development of acquired tolerance.
Thymic Influence on Immune Tolerance (1961)
- Medawar investigated the role of the thymus in
immune tolerance. His studies demonstrated that
removal of the thymus in early life resulted in a lack of
acquired immune tolerance, emphasizing the
importance of thymic function in establishing
tolerance.
These experiments were carried out by Medawar, who performed tissue
grafts on twin calves and in mice. The large number of inbred mice
available was an advantage, because there was little genetic variation
between mice from the same litter. Foreign tissue was introduced into
mouse embryos whilst still in the womb, and the young mice were then
allowed to develop normally.
When tissue grafts were performed on these mice, they had no
immune reaction if the tissue was the same type that had been
introduced in the womb. However, they reacted strongly to the
grafting of other foreign tissue. The mice were said to have
'aquired immunological tolerance' to a particular tissue.
Medawar's groundbreaking research significantly
advanced our knowledge of acquired immune
tolerance, laying the groundwork for further studies in
immunology.
Presented by:
David, Jana Manalo, Crizella Marie DJ.
Galman, John Kevin Mizobe, Gilliane Louise
Gatmaitan, Miguel Rupert Sulangi, Enjhela Mae
Macalino, Ma. Danica Ann Tolentino, Nicole
 NI
ELS
Microbiology and Parasitology

KAJ
JE R NE
The immune system is made up of cells,
lymphocytes, and antibodies that work to
neutralize antigens—substances that are alien to
the body. Niels Jerne claimed in 1955 that the
immune system works through selection and that
all types of antibodies had already developed
during the early stages of pregnancy. He claimed
in 1971 that the thymus gland is where
d e r
un
lymphocytes learn to identify the chemicals that

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belong to the body on their own. His 1974 network
theory is predicated on the notion that antibodies
have the ability to bind to one another as well as
to antigens. The immune system responds when
an antigen throws off the balance of the system.
BASEL INSTITUTE FOR IMMUNOLOGY
Natural Selection Theory of Immunology

SPECIFICITY IS PREDETERMINED
In his Natural-Selection Theory of Antibody
Formation from 1955 Jerne explains the development
of a specific antibody response in the following way.
In Jerne`s natural selection theory it is implied that
the generation of the enormous number of antibody
specificities is independent of exogenous antigens.

REACTIVITY AGAINST SELF-ANTIGENS CREATES DIVERSITY
In the second theory on the Somatic Generation of
Immune Recognition set forth in 1971 Jerne explains
how the immune system develops from stem cells to
mature lymphocytes which can react with antigen.
The theory explains how the immune system normally
matures through the influence of self antigens.
ANTIBODIES, ANTI-ANTI-BODIES
A basis for the network theory was the observation
NETWORK THEORY
Antibody 1 (Ak-1) has a structure in its variable (V) region
which can bind the antigen. The V-region of Ak-1 contains
unique structures which stimulate the production of various
anti-antibodies (Ak-2). Some Ak-2 express V-region
structures which mimic the antigen and which therefore
can stimulate Ak-1 production.
Each antibody generation induces the production of still
another and larger set of anti-antibodies in a cascade-like
manner. The various sets of antibodies stimulate or
suppress the production of each other in a complex
network. Under normal conditions the network is balanced.
However, the equilibrium is disturbed when an antigen is
introduced and binds to Ak-1. The immune system attempts
to restore the balance, i.e. it leads to an immune response.
DAVID, JANA ANTOINETTE
presented:

that antibodies can elicit anti-antibodies directed GALMAN, JOHN KEVIN

against antigen binding structures on the first GATMAITAN, MIGUEL RUPERT
antibody (Figure 1). MACALINO, MA. DANICA ANN
Moreover, anti-antibodies can stimulate the MANALO, CRIZELLA MARIE
production of still another generation of antibodies, MIZOBE, GILLIANE LOUISE
anti-anti-antibodies. SULANGI, ENJHELA MAE
TOLENTINO, NICOLE
 GE
O R G E S J.
Microbiology and Parasitology

F.
KÖ H
LER
Antibodies, which are substances foreign to the body,
are neutralized by cells, lymphocytes, and other
components of the immune system. Although each
cell can only make one type of antibody, we have
millions of distinct types of antibodies. Tumors can
occasionally develop when a certain type of antibody-
forming cell develops improperly. George Köhler and
Cesar Milstein devised a technique in 1975 for fusing
these tumor cells with immune cells against a
particular antigen to generate monoclonal antibodies,
which are antibodies of the same type.

HYBRIDOMA
MONOCLONAL ANTIBODY

In the body’s immune system, cells called lymphocytes secrete

various types of antibodies, whose function is to attach themselves to
antigens (foreign substances) that have entered the body. The
immune system maintains a vast variety of antibodies, with each
type able to attach itself to a matching site on the surface of a
particular type of antigen (e.g., a particular species or strain of
bacteria). Köhler and Milstein saw that if a way could be found to
clone lymphocytes—to cause them to subdivide indefinitely in a
culture medium—then the antibody molecules secreted by the
resulting population would all be identical. Lymphocytes are short-
lived, however, and cannot be cultivated satisfactorily. Köhler and
Milstein solved this problem by inducing lymphocytes to fuse with the
cells of a myeloma (a type of tumour), which can be made to
reproduce indefinitely. The resulting hybrid cells produced a single
species of antibody while perpetuating themselves indefinitely.

He and Rusconi generated the first transgenic mice with

The basic stages involved in creating a hybridoma. Spleen
cells are extracted from animals, most commonly mice,
after they have received a particular antigen vaccination.
After that, these cells are combined with myeloma cells that
are kept in culture in a lab. A hybridoma is the term used to
describe the result of this union. It is surprising to learn that
a hybrid of two cells is capable of both survival and division.
The spleen cells control the manufacture of antibodies with
a predetermined specificity in this hybrid, while the
myeloma cells provide the ability to survive. Hybridoma cells
can proliferate through specific configurations, whereas
separate myeloma cells cannot. To isolate colonies derived
from single hybrid cells, the resulting hybrids are
propagated in a very diluted form. The clones that produce
the particular antibodies are identified using a sensitive
approach. After then, an individual hybridoma can be
employed indefinitely to produce highly specific antibodies
in the future.
genes coding for both the heavy and light chain
domains in an antibody. Their results were published in
Nature in March 1985. Some of the transgenic mice
Kohler and his collaborators Frank Brombacher, Marinus
Lamer and Herman Eibel developed helped demonstrate
the important role receptors of the hormone interleukin
play in the human response to parasitic infections. This
was published in The EMBO Journal 8/12 (1989), 3719-26.
DAVID, JANA ANTOINETTE MANALO, CRIZELLA MARIE
GALMAN, JOHN KEVIN MIZOBE, GILLIANE LOUISE
GATMAITAN, MIGUEL RUPERT SULANGI, ENJHELA MAE
MACALINO, MA. DANICA ANN TOLENTINO, NICOLE
 CÉSAR
MILSTEIN, PH.D
(born October 8, 1927, Bahía Blanca, Argentina—died March 24,
2002, Cambridge, England), Argentine-British immunologist who in
1984, with Georges Köhler and Niels K. Jerne, received the Nobel
Prize for Physiology or Medicine for his work in the development of
monoclonal antibodies.

Milstein studied antibodies—the proteins produced by mature B lymphocytes (plasma

cells) that help the body eliminate infections. In his research he used myeloma cells,
which are cancerous forms of plasma cells that multiply indefinitely

In 1975, working with Köhler, who was a postdoctoral fellow at Cambridge, Milstein
developed one of the most powerful tools of molecular biology: monoclonal antibody
production, a technique that allows researchers to construct cells that produce great
quantities of identical (monoclonal) antibodies, all targeted to recognize the same

L
antigen.

MONOCL ON A
The procedure involves fusing long-lived myeloma cells that do not produce
antibodies with short-lived plasma cells that produce a specific antibody. The
resulting hybrid cells, called hybridomas, combine the longevity of the myeloma cell
with the ability to produce a specific antibody and so are able to produce potentially
unlimited amounts of the desired antibody.

ANTIBODY
Monoclonal antibodies have a wide Milstein received the Royal Medal (1982) and
variety of clinical and research the Copley Medal (1989) from the Royal
applications; for example, they are Society of London. In 1983 he became head
used in pregnancy tests, in of the Protein and Nucleic Acid Chemistry
diagnosing viral and bacterial Division at the Medical Research Council
diseases, and in blood cell and tissue laboratory. In 1994 Milstein was made a
typing. Companion of Honour.