(Received, June 28, 2011)
June 11, 2001
Prof. Dr. F. Melchers
Thank you for your letter of April 6, 2001. In response to your request, I shall be pleased to summarize the three topics you asked to be dealt with.
1) What was I, and what did I do in science, before I joined the institute?
When I returned with my family from the US to Switzerland in 1965, (a move not done voluntarily, because Bill Billingham then at the University of Pennsylvania, Philadelphia offered me an assistant professorship, an offer which I could not take advantage of because of lack of an immigration visa), I was offered by Lean Lindenmann the position as a chief assistant (Oberassistent) at the Institute of Medical Microbiology, Division of Experimental Microbiology, University of Zürich. There I continued my research in transplantation immunology. In particular I followed up the ideas put down in papers with Billingham and later Streilein (Ann. N.Y. Acad. Sci.,120: 379,1964; JEM,123: 629,1966; Lancet, 1: 622,1965). These showed that mixtures of lymphoid cells from genetically different inbred strains of mice, rats and hamsters, when injected into the skins of lethally irradiated hamsters produced skin reactions of delayed type hypersensitivity character. By changing to in vitro technology, it turned out that such mixtures of immune-competent lymphoid cells when cultivated secreted into the medium some factor which, when concentrated by lyophilisation, then reconstituted 10x and injected i.d. into irradiated (but as shown later also normal) hamsters attracted polymorphonuclear (PMN) cells. To quantitate the degree of PMN accumulations, skin reactions were excised, cut into small fragments, which were trypsinized, and PMNs thus released were counted. The numbers of PMNs in skin reactions followed the degree of histoin-compatibility and immune-competence (Science, 157: 554, 1967). This factor was later called PAR for “Product of Antigenic Recognition”. As these studies elaborated it became clear that PAR must be induced by recognition of foreign transplantation antigens by immune-competent T lymphocytes. Efforts, therefore, concentrated on the (then largely mysterious) T cell receptor. In collaboration with Lindenmann, adult F1 hybrid animals from the three species mentioned were immunized with lymphoid cells from one of the parental strains. In the sera of all species of so treated animals an activity could be found which specifically inhibited recognition of transplantation antigens by cells of the immunizing parent of the other parent present on F1 hybrid cells. These data showed that F1 hybrids could form antibodies against those receptors, which they lacked for genetic reasons (Path. Microbiol., 34: 379, 1969). I think these data gave perhaps the first indication on the existence of the T cell receptor for transplantation antigens, for receptors (then called Recognition Structures, RS) could be inhibited specifically. They furthermore had to do with idiotypic problems and as a result of some correspondence with Niels Jerne, he invited me to join the Basel Institute for Immunology. This I did from spring 1971 to spring 1973. In April 1970 I was promoted to assistant professor of the Medical Faculty, University of Zürich.
2) What did I do, and achieve, while I was at the institute?
Even before joining the institute, I tried hard to replace the cumbersome PAR test by some more accepted, conventional test system, but I failed (as I did also many times later). To do this I had plenty of time, because all lyophilizers at the institute were not capable of drying the culture supernatants properly, but thawed the material and thus inactivated it. After about six months I went to see you, Fritz, and declared that if I do not get the same lyophilizer as I had in Zürich, and which worked very well, I would return to Zürich. I then got it. This, by the way, turned out to be the main problem of the fact that, with the exception of Hans Binz (e.g. J. Immunol., 111:1108, 1973), nobody could reproduce the PAR test. Although I instructed a number of people on the problem of lyophylization, nobody seemed to take the problem of thawing and inactivation seriously. At the institute, the finding made in Zürich that an allo-antiserum-A anti-B carried the same “recognition sites” as do immune-competent-A T-cells, was followed up. Antibodies raised against such allo-antibodies blocked the T-ceIl receptor just as specifically as did the cell-induced antibodies described above. Thus, a possible similarity between recognition structures on immune-competent T-cells and the antigen-binding sites of allo-antibodies aimed at the same target could be shown (JEM, 134:1083, 1971, Eur. J.Immunol., 2: 109, 1971). In addition, the “education” of T- and B- (thymus) cells to recognize transplantation antigens was studied and revealed activity by their capacity to form aIlo-antibodies and induce formation of anti-RS antibodies (Cell. Imm., 8:177, 1973). Also, studies on the nature of PAR showed that it is formed whenever T- but not B-cells were confronted with allo-antigens (Nature, 246:351, 1973). Using congenic strains of mice, the fine structure of T-cell receptors for H-2 antigenic specificities could be demonstrated (Eur. J. Immunol., 3: 164, 1973). Furthermore, it was found that mice could be immunized against abolition of tolerance by heavy doses of otherwise effective transplantation tolerance-breaking cells due to induced formation of anti-RS antibodies in “immunized” tolerant mice (Eur. J. Immunol., 3:156, 1973).
3) What did I become after left the institute, and what impact did my work at the institute have on my career afterwards?
My stay at the institute and the “call” by Niels Jerne to become a permanent member, certainly helped that I was promoted to the position of an extraordinary professor in 1975. Before that, alas, my salary dropped by about 20 percent! Unfortunately, I had very little collaboration during my stay at the institute, most likely because of my unconventional test system and a general lack of urgent interest in transplantation immunology. Only J. F. A. P. Miller showed interest in acollaboration, but one test not giving the expected result, stopped it. Later on, Hans Binz and Hans Wigzell succeeded in confirming many aspects of results obtained with the PAR assays, using different immunization procedures allowing conventional tests.
Well, Fritz, I hope this is what you expected in your letter. As you wished, I shall also put this down this in handwriting, but in case you have difficulties in deciphering my hieroglyphs, this should help as the "Rosetta stone".
I hope sincerely that your “state of transition” will soon end and will find a satisfactory solution.