Presentation Speech by Professor Lars Klareskog of the Nobel Committee at the Karolinska Institute

Translation of the Swedish text

Your Majesties, Your Royal Highness, Ladies and Gentlemen,

Peter Doherty and Rolf Zinkernagel are receiving their Prizes for their discoveries concerning the specificity of the cell mediated immune defense, or to be more precise – they discovered how white blood cells recognize and kill virus-infected cells. During the following few minutes I will try to describe why this is so remarkable.

Let us thus try to imagine the extremely dangerous environment in which we live. We are surrounded by a wide array of microorganisms which are universally present in our environment. Our remedy is the immune system which, however, faces a formidable task. Not only are microorganisms numerous and ubiquitous. The immune system must be able to distinguish between friendly microbes and hostile, between foreign material and self structures. And not only that. Certain invaders – for example viruses – utilize host cells for their own replication and hide inside these same cells.

When Peter Doherty and Rolf Zinkernagel began their research in the late 1960s and early 1970s, it had already been discerned how antibodies, the circulating defense molecules, recognize and kill their targets such as bacteria. It was far less well understood, however, how the cellular immune effectors, white blood cells, recognize and kill virus-infected cells without destroying the normal uninfected cells.

Another observation that gave rise to both fascination and problems was the finding of each individual’s immunological uniqueness. The small, but important inter-individual differences that exist between molecules called transplantation antigens are what our white blood cells recognize as “self” or “foreign”. But the reason behind nature’s creation of this immunological uniqueness, this obstacle to transplantation, remained a big mystery.

Rolf Zinkernagel began in 1973 the kind of “journey for knowledge” which is open to the curious scientist. He came from Switzerland to Robert Blanden’s laboratory at the John Curtin School of Medical Research in Canberra, Australia, where he met Peter Doherty. Together they studied basic aspects of the immune defense against virus infections in different strains of mice. They found that white blood cells – or more precisely killer T cells – from one mouse strain recognize and kill virus-infected cells from another mouse strain only if the two mouse strains carry the same variant of transplantation antigens. From this seemingly technical and simple observation Doherty and Zinkernagel, and subsequently a whole generation of immunologists, were able to find new approaches and new solutions to a series of fundamental immunological problems.

It became possible to understand that the true function of transplantation antigens is not to provide an obstacle to transplantation. Instead, their function is to bind and present molecules from viruses and other microorganisms to white blood cells in such a way that the white blood cells understand whether they should become aggressive or stay calm. As a consequence it became obvious how each individual, thanks to his/her unique set of transplantation antigens, also carries his/her unique immune system.

It also became possible to understand why evolution has created these large immunological differences between us as individuals within a species. Immunological diversity is advantageous for the single individual as well as for the species. Thus, there will always be some individuals that survive even severe epidemics. In return, individuals carrying a certain variant of transplantation antigens have an increased susceptibility to autoimmune diseases such as rheumatoid arthritis or multiple sclerosis, and this is possibly the price that these individuals pay for the fact that their forefathers survived a severe epidemic.

It is most encouraging, however, that this and subsequent research now makes it easier not only to understand, but also to change – if not the world, then the immune system. Our increased knowledge enables us to strengthen beneficial immune reactions, for example in cases of otherwise insufficient responses towards invading microorganisms or against cancer metastasis. Our knowledge should also enable us to diminish or change unwanted immune reactions towards the body’s own tissue, such as those occurring in rheumatic diseases.

The discoveries made by this year’s Nobel Laureates thus illustrate how findings within basic biological research may give rise to conclusions with wide implications for society – such as the biological advantage of diversity – and to fundamentally new therapeutic approaches in clinical medicine.

Peter Doherty and Rolf Zinkernagel,

Your discoveries concerning the specificity of the cell-mediated immune defense have deeply influenced the understanding of fundamental issues in basic and clinical immunology. On behalf of the Nobel Assembly at the Karolinska Institute I wish to convey to you my warmest congratulations and I now ask you to step forward and receive your Nobel Prizes from the hands of His Majesty the King.