1996 Nobel Prize in Physiology or Medicine

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Mon Oct 7 04:42:53 EST 1996


The Nobel Assembly, Karolinska Institutet
Press Release October 7, 1996


The Nobel Assembly at the Karolinska Institute has today decided to award
          the Nobel Prize in Physiology or Medicine for 1996

                          jointly to

              Peter C Doherty and Rolf M Zinkernagel

                 for their discoveries concerning

         The Specificity of the Cell Mediated Immune Defence


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Summary

Peter Doherty and Rolf Zinkernagel have been awarded this year's Nobel Priz=
e
in Physiology or Medicine for the discovery of how the immune system
recognizes virus-infected cells. Their discovery has, in its turn, laid a
foundation for an understanding of general mechanisms used by the cellular
immune system to recognize both foreign microorganisms and self molecules.
This discovery is therefore highly relevant to clinical medicine. It relate=
s
both to 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.

The two Nobel Laureates carried out the research for which they have now
been awarded the Prize in 1973-75 at the John Curtin School of Medical
Research in Canberra, Australia, where Peter Doherty already held his
position and to which Rolf Zinkernagel came from Switzerland as a research
fellow. During their studies of the response of mice to viruses, they found
that white blood cells (lymphocytes) must recognize both the virus and
certain self molecules - the so-called major histocompatibility antigens -
in order to kill the virus-infected cells. This principle of simultaneous
recognition of both self and foreign molecules has since then constituted a
foundation for the further understanding of the specificity of the cellular
immune system.

The background to the Laureates' research

The immune system consists of different kinds of white blood cells,
including T- and B- lymphocytes whose common function is to protect the
individual against infections by means of eliminating invading
microorganisms and infected cells. At the same time they must avoid damagin=
g
the own organism. What is required is a well developed recognition system
that enables lymphocytes to distinguish between on the one hand
microorganisms and infected cells, and on the other, the individual=B4s nor=
mal
cells. In addition, the recognition system must be able to determine when
white blood cells with a capacity to kill should be activated.

In the early 1970s when Peter Doherty and Rolf Zinkernagel had begun their
scientific work within immunology, it was possible to distinguish between
antibody-mediated and cell- mediated immunity. It was known that antibodies
that are produced by B-lymphocytes are able to recognize and eliminate
certain microorganisms, particularly bacteria. Far less was known about
recognition mechanisms in the cellular immune system, for instance in
conjunction with the killing of virus-infected cells by T-lymphocytes. One
area where cellular immunity had previously been studied in some detail was=
,
however, transplantation biology. It was known that T-lymphocytes could kil=
l
cells from a foreign individual after recognition of certain molecules - th=
e
major histocompatibility antigens - in the transplant.

The discovery

Rolf Zinkernagel and Peter Doherty used mice to study 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 cell=
s
from another strain of mice. What decided 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.
Zinkernagel's and Doherty's findings, which were published in Nature in 197=
4
(1,2), demonstrated conclusively the requirement for the cellular immune
system to recognize simultaneously both 'foreign' molecules (in the present
case from a virus) and self molecules (major histocompatibility antigens).
What also became obvious was the important function of the major
histocompatibility antigens (in man called HLA-antigens) in the individual=
=B4s
normal immune response and not only in conjunction with transplantation.

The discovery has given an impetus to later research

Zinkernagel's and Doherty=B4s findings had an immediate impact on
immunological research. The wide relevance of their observations concerning
the specificity of the T-lymphocytes became apparent in many contexts, both
in regard to the ability of the immune system to recognize microorganisms
other than viruses, and in regard to the ability of the immune system to
react against certain kinds of self tissue. To explain their findings, the
two scientists subsequently devised two models; one 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. (Fig.) Both the experimental finding=
s
and the theoretical models became immensely important in later research.
Within a few years, it had been demonstrated 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. Therefore, the principle of simultaneous
recognition is essential for the ability of the immune system to distinguis=
h
between 'self' and 'non-self'.

Further molecular research has both confirmed Zinkernagel's and Doherty's
models and clarified the structural basis of their discovery - that a small
part (a peptide), for example from a virus, is directly bound to a defined
variable part of the body=B4s own histocompatibility antigens, and that thi=
s
complex is what is recognized by the specific recognition molecules of T-
lymphocytes (T-cell receptors). Taken in all, the clarification of the
recognition mechanisms of the T-cells within the cellular immune system has
fundamentally changed our understanding of the development and normal
function of the immune system and, in addition, has also provided new
possibilities for the selective modification of immune reactions both to
microorganisms, and to self tissues.

Relevance for clinical medicine

Many common and severe diseases depend on the function of the cellular
immune system and consequently on its mechanisms for specific recognition.
Although this naturally applies to infectious diseases, this is also true o=
f
a number of chronic inflammatory conditions such as rheumatic diseases,
diabetes and multiple sclerosis. Where infectious diseases are concerned,
the new knowledge provides a better platform for the construction of new
vaccines; one can ascertain exactly what parts of a microorganism are
recognized by the cellular immune system, and can specifically focus the
production of the vaccine on those parts. Furthermore, regard is paid to th=
e
fundamental principles formulated by Doherty and Zinkernagel in trials with
vaccination against the emergence of metastases in certain forms of cancer.
In many chronic inflammatory diseases, better explanations have been
provided for the associations between disease susceptibility and the
histocompatibility antigen type carried by an individual. The research that
followed from the now awarded discovery has also provided openings for
selectively diminishing or altering immune reactions that play a central
role in inflammatory diseases.

References

1. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated
cytotoxicity in lymphocytic choriomeningitis within a syngenic and
semiallogeneic system. Nature 248, 701- 702, 1974.

2. Zinkernagel RM, Doherty PC. Immunological surveillance against altered
self components by sensitised T lymphocytes in lymphocytic choriomeningitis=
.
Nature 251, 547-548, 1974.

3. Doherty PC, Zinkernagel RM. A biological role for the major
histocompatibility antigens. Lancet, 1406-1409, 1975.

4. 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.

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 PETER C DOHERTY, born October 15, 1940, Australia
 Address: Department of Immunology, St. Jude Children's Research Hospital,
          332 North Lauderdale, Memphis, Tennessee 38105-2794, USA

 Academic Education:

 1962     BVSc University of Queensland, Australia
 1966     MVSc University of Queensland, Australia
 1970     PhD University of Edinburgh, Scotland

 Appointments and Professional Activities:

 1963-67  Veterinary Officer, Animal Research Institute, Brisbane,
          Australia
 1967-71  Scientific Officer, Senior Scientific Officer, Department of
          Experimental Pathology, Moredun Research Institute, Edinburgh,=20
          Scotland=20
 1972-75  Research Fellow, Department of Microbiology, The John Curtin
          School of Medical Research, Australian National University,=20
          Canberra, Australia
 1975-82  Associate Professor/Professor, The Wistar Institute,
          Philadelphia, PA
 1982-88  Professor and Head, Department of Experimental Pathology, The
          John Curtin School of Medical Research, Australian National=20
          University, Canberra
 1988-    Chairman, Department of Immunology, St. Jude Children's Research
          Hospital,
          Memphis, TN
 1992-    Adjunct Professor, Departments of Pathology and Pediatrics,
          University of
          Tennessee, College of Medicine, Memphis, TN

 Fellowships and Awards:

 1983     Fellowship of the Australian Academy of Science (FAA)
 1983     Paul Ehrlich Prize, Germany
 1986     Gairdner Foundation International Award, Canada
 1987     Fellow of the Royal Society of London (FRS)
 1993     Alumnus of the Year, University of Queensland
 1995     The Albert Lasker Medical Research Award


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 ROLF M ZINKERNAGEL, born January 6, 1944, Basel, Switzerland
 Address:  Institute of Experimental Immunology, Department of Pathology,
           University of Z=FCrich, University Hospital, Sternwartstrasse 2,
           8091 Zurich, Switzerland

 Academic Education:

 1962-1968 University of Basel, Faculty of Medicine

 1968      National Board Examination, University of Basel, Faculty of
           Medicine
 1970      MD Thesis, University of Basel, Faculty of Medicine
 1975      PhD Thesis, Australian National University, Canberra, Australia

 Appointments and Professional Activities:

 1969-1970 Postdoctoral Fellow, Laboratory for Electron Microscopy,
           Institute of Anatomy, University of Basel
 1971-1973 Postdoctoral Fellow, Institute of Biochemistry, University of
           Lausanne, Switzerland
 1973-1975 Visiting Fellow, Department of Microbiology, The John Curtin
           School of Medical Research, Australian National University,=20
           Canberra, Australia
 1976-1979 Associate (Assistant Professor), Department of Immunopathology,
           Research Institute of Scripps Clinic, La Jolla, California
 1977-1979 Adjunct Associate Professor, Department of Pathology, UCSD, USA
 1979      Member (Full Professor), Department of Immunopathology,
           Scripps Clinic and Research Foundation
 1979-1988 Associate Professor, Department of Pathology, University of
           Z=FCrich, University Hospital, Zurich
 1988-1992 Full Professor, Department of Pathology, University of Zurich,
           University Hospital, Zurich
 1992-     Head, Institute of Experimental Immunology, Zurich

 Fellowships and Awards:

 1981      Cloetta Stiftung, Zurich
 1982      Jung Stiftung, Hamburg
 1983      Paul Ehrlich Prize, Frankfurt
 1985      Mack-Forster Prize, Europ Ass Clin Inv
 1986      Gairdner Foundation International Award, Toronto
 1987      Institute for Cancer Research, New York
 1988      Louis Jeantet Foundation, Geneva
 1988      Naegeli Stiftung, Zurich
 1992      Christoforo Colombo Award, Genova
 1995      The Albert Lasker Medical Research Award





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