IMMUNOLOGISTS RECOGNIZED |
Henahan, Access Excellence
STOCKHOLM, SWEDEN (Oct.7, 1996)
Two pioneering immunologists whose work helped determine how
the immune system recognizes foreign invaders have themselves
been recognized by a foreigh body, the Nobel Foundation.
Dr.Peter Doherty (now chairman of the Dept. of Immunology at St.
Jude Children's Research Hospital in Memphis, TN) and Dr. Rolf
Zinkernagel (now head of the Institute of Experimental
Immunology at the University of Zurich) have been awarded this
year's Nobel Prize in Physiology and Medicine.
"The work fundamentally changed our understanding of the
development of the immune response. Apart from vaccines, the
work has guided attempts to use the immune system to hunt down
and destroy microscopic cancer cells that have escaped from
tumors. It has also helped scientists as they design ways to
suppress harmful immune system attacks on the body's own tissue,
as seen in multiple sclerosis and diabetes," a statement from
the Nobel Foundation noted.
The Prize recognizes research conducted by the two researchers
when they worked together in the mid-1970s at the John Curtin
School of Medical Research in Canberra, Australia. Their key
animal research showed that white blood cells (lymphocytes) must
recognize both an invading virus and certain self molecules -
the so-called major histocompatibility (MHC) antigens in order
to kill the virus-infected cells. This concept of simultaneous
recognition of both self and foreign molecules formed the basis
for a new understanding of the specificity of the cellular
The research of Zinkernagel and Doherty had an immediate and
long-lasting effect on immunological and clinical research.
Their findings on the specificity of the T-lymphocyte mediated
immune response proved a fundamental advance in the
understanding of how the immune system is able to recognize
microorganisms other than viruses, and in the understanding of
how the immune system reacts against certain kinds of self
The elucidation of the self/non-self selectivity of the immune
system advanced research in many clinical areas. It led to
advances in therapeutic efforts to strengthen the immune
response against invading microorganisms and certain forms of
cancer, and to efforts to diminish the effects of autoimmune
reactions in inflammatory diseases, such as rheumatic
conditions, multiple sclerosis and diabetes. It has also proved
to be a great advance in the field of organ transplantation.
Graphic: How a killer T lymphocyte
must recognize both the virus antigen and the self
histocompatibility antigen molecule in order to kill a
virus-infected target cell.
BACKGROUND: THE ORIGINAL RESEARCH
When Doherty and Zinkernagel began their work, the existence of
antibody-mediated and cell- mediated immunity was known. More
was known about how antibodies produced by B-lymphocytes were
able to recognize and eliminate certain microorganisms,
particularly bacteria, than about the recognition mechanisms in
the cellular immune system. Transplantation studies had shown
that T-lymphocytes could kill cells from a foreign individual
after recognition of certain molecules - the major
histocompatibility antigens - in the transplant.
The two scientists conducted animal studies to determine how the
immune system, and particularly T-lymphocytes, could protect
animals against infection from a virus able to cause meningitis.
Infected mice developed killer T-lymphocytes, which in a
test-tube could kill virus- infected cells. But there was an
unexpected discovery: the T-lymphocytes, even though they were
reactive against that very virus, were not able to kill
virus-infected cells from another strain of mice. The
determining factor of whether or not a cell was eliminated by
these killer lymphocytes was not only if they were infected with
the virus, but also if they carried the "correct" variant of
histocompatibility antigens, those of the infected mouse itself.
In a nutshell, the researchers work confirmed the requirement
for the cellular immune system to recognize simultaneously both
'foreign' molecules and self molecules (major histocompatibility
antigens), emphazising the role of the major histocompatibility
antigens in the normal immune response and not only in
conjunction with transplantation.
The researchers developed two models to explain their findings.
The first model was based on a single recognition of 'altered
self'' (when the histocompatibility antigen has been modified
through association with a virus), the other on a 'dual
recognition' of both foreign and self. (see illustration).
Subsequent research in later years showed that the set of the T-
lymphocytes that are allowed to mature and survive in an
individual is determined by the ability of the cell to recognize
the transplantation antigens of the individual. The original
principle of simultaneous recognition was proved essential for
the ability of the immune system to distinguish between 'self'
Additional molecular research has both confirmed Zinkernagel's
and Doherty's models and clarified the structural basis of their
discovery. Structurally, a small part (a peptide), for example
from a virus, is directly bound to a defined variable part of
the body's own histocompatibility antigens, and that this
complex is what is recognized by the specific recognition
molecules of T- lymphocytes (T-cell receptors).
Related information on the
AE: Nobel 1995: Genetics
1996 Nobel Prize for Medicine
- Zinkernagel RM, Doherty PC. Restriction of in vitro T
cell-mediated cytotoxicity in lymphocytic choriomeningitis
within a syngenic and semiallogeneic system. Nature 248, 701-
- Zinkernagel RM, Doherty PC. Immunological surveillance
against altered self components by sensitised T lymphocytes in
lymphocytic choriomeningitis. Nature 251, 547-548, 1974.
- Doherty PC, Zinkernagel RM. A biological role for the major
histocompatibility antigens. Lancet, 1406-1409, 1975.
- Zinkernagel RM, Doherty PC. MHC restricted cytotoxic T cells:
Studies on the biological role of polymorphic major
transplantation antigens determining T cell restriction
specificity. Advances in Immunology 27, 51-177, 1979.