By Sean 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 immune system.

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 tissue.

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.

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' and 'non-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).

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AE: Nobel 1995: Genetics of Development.

1996 Nobel Prize for Medicine

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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