Carl Prausnitz: A personal memoir

The ALLERGY ARCHIVES Pioneers and Milestones Sheldon Cohen, MD, Editor Special note Murray Dworetzky, MD, one of the two founding editors of The Allergy Archives, has retired from an active role in the editing of this series in order to devote more time to his many other professional interests. He will continue to contribute historical commentary as his schedule allows. We are indebted to Dr Dworetzky for his energy and commitment in launching a feature that documents the fascinating history of our specialty.

Carl Prausnitz: A personal memoir

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FIG 1. Carl Prausnitz-Giles.

In 1935, Carl Prausnitz (Fig 1), at age 59 years and the height of an illustrious medical and scientific career, decided to forsake all academic and research fields and become a general practitioner on the Isle of Wight. Troubled by the dismaying changing circumstances being created in Germany by the Nazi regime, he left for England. There he took the maiden name of his mother, Giles. Dr Giles’ patients quite often referred to him as Father Giles; indeed, he was a paternal figure to many of them. They did not know that they were being looked after by an internationally known professor who had not only left his country of birth and education but had also given up all academic work in which he was one of the founders of the field of modern bacteriology and was a ‘‘father of the new medical science of allergy and immunology.’’ I consider it a privilege to have known him. Carl Prausnitz was born in Hamburg in 1876, and known as Dr Giles, he died on the British Isle of Wight in 1963. His father was a physician, and his mother was from the Isle of Wight. Often, as a schoolboy, he spent his summer holidays on the island, and therefore from a very early age he was bilingual in German and English. In 1899, he married the daughter of a Professor of Law at Breslau. Prausnitz studied medicine in Leipzig, Kiel, and Breslau and qualified in 1901. He became especially interested in bacteriology, and in 1903, he was awarded an MD for his thesis on cholera vibriae. In a tape recording of his life, he began the recounting of his career with 1902, when he started working with Professor William Dunbar at the State Hygienic

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Institute in Hamburg during an outbreak of cholera in that city. Early on, he also became interested in allergic phenomena, especially hay fever, a complaint that both he and his chief suffered. In 1905, Prausnitz came to England, where until 1908, he worked at the Royal Institute of Public Health and Hygiene as a demonstrator of bacteriology and comparative pathology. His position provided him the opportunity to meet visiting specialists in bacteriology and hygiene, who were among the foremost scientists of the day. Also, assignments to translate into English endowed series of lectures for publications in the institute’s journal led to rewarding interactions and associations that included lasting friendships with Paul Ehrlich and Richard Pfeiffer. Meanwhile, he passed the British Medical qualification, and from 1908 to 1910, he was assistant bacteriologist to the Metropolitan Asylums Board in London. But uninspired with this job and having received an invitation to join Pfeiffer as head of the hydrophobia department of his institute, in 1910, he returned to Breslau, and in 1912, he was made Privatdozent of Bacteriology and Hygiene of the university. For Prausnitz, this marked the beginning of many years of ‘‘affection, friendship, and learning from a wise and kind man,’’ Pfeiffer, who was his mentor and then associate. In 1914, with the outbreak of World War I, Pfeiffer left the institute for military duty as a hygiene inspector and advisor. The following year, Prausnitz was able to

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join him as his assistant in the 14th Army Corps. Even in military service, Prausnitz’s language skills led to a crossing of paths with infectious disease pioneers. Seeking critically needed tetanus antiserum, Pfeiffer and Prausnitz traveled to tap the known supply at the Institut Pasteur in Lille, after the city’s fall to the German army. Only Prausnitz’s translation of laboratory protocols, pointing to use of an expended pigeon in experiments that led to the development of BCG vaccine and not for carrying covert messages, saved Leon Calmette and Camille Guerin from the fate of (mistakenly) accused spies. In 1923, Prausnitz became deputy professor at the University of Greifiswald. In 1926, he was named professor of bacteriology and hygiene at Breslau (later called Wroclaw, Poland), succeeding his former chief and revered mentor Richard Pfeiffer, who then had been working on rabies. Prausnitz took a very active part in the work of the Health Organization of the League of Nations, and in 1928, he was seconded to the Secretariat for a year. Some idea of Prausnitz’s philosophic thoughts can be gleaned from a consideration of his hopes that would arise from the work of the League of Nations. In a lecture he gave in 1931 to the Medical Section of the Silician Society for Vaterlandische Cultur, he closed with the following remarks (translated): ‘‘As we now see, just over ten years from the end of the World War, there has grown up a large new organization, whose sole task is to wage war against infectious diseases and social ills. Its functions begin when all nations have common interests. Through its work the investigators and medical officials of various countries are brought into close contact, they learn the methods used in other countries, they gain understanding of neutral difficulties and needs, national restraints are overcome and new friendships are made. And the same is happening with the nations themselves. In these ways the hygiene organization performs a real service for the peace of the world.’’ Fluent in English, French, and Italian, and partially in Russian, he served several assignments for the Health Organization and the League itself. Sadly, his eminent stature and accomplishments meant little to those concerned with Germany’s rising tide of National Socialism. His representation and involvements in activities and functions of the organization and his numerous scientific friendships and interactions throughout Europe were presumably looked on with disfavor by the political party coming into power. Although raised as a Christian in the Lutheran faith and decorated with the Iron Cross for World War I service, the anti-Semitic factor took precedence; his paternal grandfather was Jewish. Scientifically, it similarly mattered little that he published more than 100 articles, mainly on bacteriology but also on disinfectants, cholera, typhoid, typhus, the Wasserman reaction, bacteriophage, and tissue culture. The function of his

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701 FIG 2. Heinz Ku¨stner.

position in Breslau became increasingly difficult to conduct. Soon after the Nazis came to power in 1933, he resigned from the faculty and left Germany for England, where after a year or two in temporary laboratory positions, he entered general medical practice. He once said, ‘‘Never again shall I set foot in Germany.’’ However, in 1958, he was persuaded by Karl Hansen to return to his native land to receive the Aronson award of the Robert Koch Institute in Berlin and again in 1960 to Hamburg for the honorary MD. At the turn of the century, after working with Dunbar, Prausnitz never lost his interest in allergy. Furthermore, the article published in 19211 made him internationally famous. Before his seminal report was published, allergic complaints were considered to be produced by poisons. Twenty years earlier, Richet and Portier experimentally worked with known acute poisons. When injecting their experimental dogs, a second very small and similar dose 22 days later caused anaphylaxis, and death of the dog was not expected, but perhaps like the discovery of penicillin, as Louis Pasteur observed, ‘‘in the fields of observation, chance favours only the minds that are prepared.’’2

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When at the Hygienic Institute with Pfeiffer, Prausnitz had a 24-year-old scientist, Heinz Ku¨stner (Fig 2), working with him; Ku¨stner had been allergic to fish since the age of 6 years. His immediate fish-allergy responses were quite unusual in that he could eat raw but not cooked fish. Ku¨stner (1897-1963), then a junior scientist in Prausnitz’s department at the Institute of Hygiene in Breslau, later became a very well known and respected German gynecologist. As Professor of Obstetrics and Gynecology at the University of Leipzig, he was recognized throughout Germany for his textbook Geburtshiffe Frauenheilkinde, which went through 10 editions between 1932 and 1965. Ku¨stner’s acute immediate fish-allergy reaction provided an ideal opportunity for Prausnitz to demonstrate the passive transfer of fish antibodies to the skin of a subject not sensitive to fish. Prausnitz told me that Ku¨stner most annoyingly was very disinterested in these experiments. Indeed, when Prausnitz requested a similar experiment, transferring his own pollen sensitivity to Ku¨stner’s arm, it required considerable persuasion to get Ku¨stner to agree to accept the injection of his serum. The experiment was unexpectedly and, at the time, inexplicably negative. Ku¨stner remained forever disinterested in allergy and immunity, and it was typical of Prausnitz’s generosity, allowing Ku¨stner’s name to be included as a coauthor for the article that he alone wrote. Prausnitz realized that he could eat the fish that caused Ku¨stner’s immediate reaction with impunity. Therefore it was not a poison, but Ku¨stner must have produced antibodies to the antigens of fish. He presumed correctly that the antibodies were in Ku¨stner’s blood serum and could be demonstrated by transferring them to the cells of the skin of his (Prausnitz’s) forearm. In the article Prausnitz referred to himself as ‘‘normal.’’ What he must have meant was that he was not a fish-sensitive subject because, far from normal, he had suffered severely from summer hay fever caused by grass pollen. Ku¨stner’s blood serum was injected in various dilutions intradermally into Prausnitz’s forearm. When the irritation of reaction had settled by the next day, he injected a fish solution into the areas of his skin that had received Ku¨stner’s serum and also in noninjected areas. Only the former areas reacted with an immediate wheal-and-flare reaction. He noted that ‘‘after repeated performance of intradermal injections of fish extract there resulted a local reduction of sensitivity that lasted for several weeks.’’ Many years later, when Prausnitz was living permanently in England, he became friendly with Professor Robin Coombs and visited him in Cambridge. From this association, Prausnitz translated his German article into English in the widely read book by Gell and Coombs, Clinical Aspects of Immunology.3 Earlier ideas of toxins and antitoxins in allergic diseases, particularly those put forward by Dunbar at

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the turn of the century, were forever changed. Thus even though the allergic antibody had not yet been characterized, a scientific immunologic basis for investigating allergic phenomena had thereby been initiated. For many years after 1921, the PrausnitzKu¨stner reaction remained the classical method of demonstrating skin-sensitizing antibodies. The spelling of the 2 names and possibly the pronunciation had its difficulties, and therefore ‘‘P-K test’’ soon became a term used internationally when describing the reaction. What seems so strange about this article, and indeed that it was ever published, is Prausnitz’s statement that ‘‘it was not possible with this technique to transfer sensitivity to pollen protein, horse serum or tuberculin.’’ His explanation of the failure to transfer pollen protein antibodies was not at all persuasive that ‘‘perhaps we might have succeeded with the sera of persons more highly sensitive than those available to us.’’ We know that Prausnitz clinically was very allergic to grass pollen because he had pollen-associated asthma in the summer. But his blood serum was transferred to Ku¨stner’s arm, and Ku¨stner had reported that there was no reaction to pollen at the injection sites. This failed experiment always worried me. In 1963, I gave a lecture entitled, ‘‘Allergy; Immunity gone wrong.’’4 Prausnitz, then known as Dr Giles, was in my audience. When, after the lecture, he came up to me to ask a question, it gave me the opportunity to ask him why he believed that the passive transfer of his pollen antibodies had failed. I said I had mild hay fever in the summer, but I could dilute my blood a hundred times and still obtain a passive transfer of my pollen antibodies. Prausnitz’s reply was quite unexpected. He said he had recently returned to Germany and had taken the opportunity to visit his old friend Ku¨stner and ask him the same question that I had just asked. Ku¨stner, who by then had become a famous obstetrician, told Prausnitz that he was never keen on the passive transfer experiments and that he was ‘‘not sure that he (Prausnitz) was healthy.’’ Therefore he boiled the blood for 10 minutes before finally injecting it into the skin of his arm. In the original article it was stated that ‘‘the active principle is insoluble in cold and warm alcohol and ether and it is non-dialyzable, is speedily inactivated by acids but not by alkalis, pepsin or trypsin.’’ It is noteworthy that there was no mention of the effect of heat on the active principle. In 1955, Prausnitz published an article, ‘‘The passive transfer of allergy,’’5 in which he wrote that allergy can occur in animals and passive transfer of allergic antibodies of human subjects can be transferred to the experimental guinea pig. Other workers had sensitized human subjects by means of intravenous injection of specific antibodies, but Prausnitz stated that to avoid generalized sensitization, he carried out his experiment to

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demonstrate local sensitization in the skin. In his review article of 1955,5 he referred to De Besche,6 who in 1923 used his method of passive transfer in cases of horse-induced asthma and hay fever. Freeman7 had also carried out numerous tests of a similar kind in pollen allergy. At that time, in 1955, Prausnitz did not know why his own pollen transfer tests had failed. Prausnitz admitted that passive transfer of allergic serum had its disadvantages because (1) it does not succeed in every case, presumably referring to his own failed pollen antibody transfer to Ku¨stner, and (2) there is a chance of transferring some diseases, especially serum hepatitis. This was written before the worldwide outbreak of AIDS. It now would not be ethical to carry out a P-K test, especially since the IgE antibody has been characterized. He further pointed out that generalized sensitization, as opposed to his described experimental local skin sensitization, had been known since 1919, when transfusion of blood from a patient with horse allergy had sensitized a healthy person to horse. Today, in 2004, it continues to be appreciated that blood transfusions, when taken from an allergic subject, might still temporarily sensitize a nonallergic subject. The methodology of Prausnitz’s research on cotton spinner’s asthma is most illuminating.8 This work was carried out while he was an honorary research fellow in Professor M. B. Maitland’s Department of Bacteriology at the University of Manchester, with support for Professor Prausnitz coming mainly from a personal grant received from the Rockefeller Foundation in New York. In the preface of the report, it was noted that the Medical Research Council was fortunate in securing the services of a distinguished investigator in industrial medicine. In that study Prausnitz showed that there was an allergic sensitivity in all patients with cotton dust–induced respiratory disease and concluded that, in this respect, it was related to ordinary asthma. At the time of his investigations, it was believed that histamine, which is present in cotton dust, was the cause of the disease. His observations, however, did not support that contention. Monday morning ‘‘mill fever’’ rather strangely did not occur at work during the remaining days of the week, but ultimately, if the workers remained in the dusty atmosphere, the complaint developed into a ‘‘typical form of asthma.’’ Prausnitz mentioned that cotton operatives in Germany, Russia, and America were sensitive to cottonseed protein, as detailed in the article by Brown from Washington.9 Additionally, it was noted that more than half of the cotton dust that caused symptoms consisted of particles of a size less than 0.2 lm. It is noteworthy that Prausnitz found that on collecting cotton dust from mills, he experienced sneezing and irritating cough, followed by a rather severe attack of asthma.

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Many lung function tests were performed, but provocation tests were not. He did, however, note the difference in lung function tests between workers who had symptoms from cotton dust and the control group who had no symptoms. Intradermal skin tests resulted in a primary toxic response in healthy and affected cotton workers, but superimposed secondary allergic reactions occurred only in affected cotton spinners. He carried out 4 intradermal injections of 0.1 mL of extract on his own abdomen with the feature that ‘‘in order not to complicate the results anaesthesia was dispensed with.’’ The examination of the biopsy sections 16 hours after injection showed leukocytic infiltration, no plasma cells, and only occasional mast cells, which was in fact a reaction of inflammation. Work during the 2 and a half years that Prausnitz researched cotton spinner’s chest disease was very eruditely described in his report.8 He wanted to continue this study but failed to obtain a further research grant. He was unhappy with his findings, especially because he definitely had shown only that the disease was not caused by the histamine content of the cottonseed. Offering a rather negative conclusion, he stated quite simply that if the histamine content had been the cause, all workers would have been affected. The allergic cause, he thought, was the most important factor causing symptoms, but the associated toxic effect of the dust was a complicating influence. In 1935, Prausnitz joined his boyhood friend Dr James Williamson in general practice at Ventnor, Isle of Wight, a locale near where his mother came from and where he, as a boy, had spent many pleasant holidays. He then changed his name to Prausnitz-Giles (Giles being his mother’s family name) and became a British citizen in 1939. Most of the information on Prausnitz-Giles has been gratefully received from Dr Alan Champion, who describes himself as the junior partner of one of the father figures of the science of allergy and immunology. When Dr Giles gave up full-time research work and went into general practice in Ventnor, to begin with, he had doubts about his capability to deal with any obstetric matters. However, very soon, not only did he become a very successful and loved general practitioner, he also became involved in many of the island’s local activities. Champion began his association with Dr Giles in 1957 and found that it was a great privilege to work with him and be taught by such a compassionate and caring doctor and friend; Giles certainly was loved by his patients for his very personal caring interest in them. He himself said that his time in general practice was the happiest of his life because he was personally involved with his patients’ problems. It must have been unusual for a general practitioner to measure his patients’ blood urea and, if necessary, red and white blood cell counts in a laboratory in the office surgery. He was particularly delighted when he retired in 1961 that his patients donated to a fund with which

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he bought a new microscope with photographic attachments. In Prausnitz-Giles obituary, not written until 1966,10 it was stated that he showed no malice to anyone. The same journal feature contained a note quoted from Dr Claude Dolman, Professor of Bacteriology, Immunology, and Preventive Medicine, at the University of British Columbia, Vancouver, who had spent a weekend with Dr Giles in March 1961: Dolman wrote ‘‘his natural enthusiasm and compassion, and a keen sense of drama, were reflected in his voice as he recounted some of his experiences into a tape recordera without rehearsals or notes of any kind, and produced a performance of first-class historical interest and genuine histrionic ability.’’11 Dr Giles never really retired. Only a year or 2 before the recorded conversation with Professor Dalman, his name hit the headlines of the national dailies, when, carrying his medical bag, he climbed the 750 feet on the top of Simbolica’s Dam and there rendered first aid to an injured holiday maker. By 1962, his health began to fail, but nevertheless, his intellectual capacity remained unimpaired until the end. While on his death bed, he dictated a letter addressed to the editor of the British Medical Journal in which he commented on an article concerned with hypnosis and passive transfer.12 When published a few weeks later, the letter13 was accompanied by a note of his passing.b Prausnitz had suffered a great deal from the turn of political affairs in Germany, but this was a subject he would never discuss in later years. We who were privileged to know him can understand why there was such loyalty to him when he was a professor in Germany and why later such affection was shown by his patients for this very lovable man. His voice recorded on the tape remains always with these memories. A.W. Frankland, DM, FRCP London Allergy Clinic

Consultant Emeritus St Mary’s and Guy’s Hospitals London, United Kingdom

REFERENCES 1. Prausnitz C, Ku¨stner H. Studien iibu die Heberernpfindlickeit. Zbl Bakt Abt I Orig 1921;86:160-9. 2. Vallery-Radot R. La ville de Pasteur. 2nd ed. Paris: Libraire Hackette; 1924, p. 88. 3. Gell PGH, Coombs RRA, editors. Clinical aspects of immunology. Oxford: Blackwell; 1962. p. 808-16. 4. Frankland AW. Allergy: immunity gone wrong. Proc R Soc Med 1973;66:365-8. 5. Prausnitz C. The passive transfer of allergy. Int Arch Allergy 1955; 6:260-9. 6. De Besche A. Studies on the reactions of asthmatics on a passive transfer of hypersusceptibility. Am J Med Sci 1923;166:265-75. 7. Freeman J. Discussion on paroxysmal rhinorrhoea. Proc R Soc Med Sec Laryngol 1924;18:29-32. 8. Prausnitz C. Investigations on respiratory dust diseases in operatives in the cotton industry. London: Medical Research Council; 1936, Special Report Series no. 212. 9. Brown GT. Cottonseed and kapok sensitization. JAMA 1929;93: 370-4. 10. Downie AW. Obituary Carl Prausnitz (Giles). J Path Bact 1966;92: 242-6. 11. Dolman C. Personal communication. In: Downie AW, editor. Obituary Carl Prausnitz (Giles). J Path Bact 1966;92:246. 12. Black S. Shift in dose-response of Prausnitz-Ku¨stner reaction by direct suggestion under hypnosis. BMJ 1963;990-2. 13. Prausnitz-Giles C. Hypersensitivity and hypnosis [correspondence]. BMJ 1963;1287.

NOTES a Through the courtesy of Dr Alan Champion of Ventnor, Isle of Wight, United Kingdom, a copy of this tape recording of Carl Prausnitz-Giles’ oral history has been given to and placed in the archives collection of the History of Medicine Division, National Library of Medicine, National Institutes of Health, Bethesda, Md, for availability to scholars and historians whose research is relevant to the subject of this work. b Addendum to Prausnitz-Giles C. Oral history. doi:10.1016/j.jaci.2004.06.040

Excerpts from a taped reminiscence by Dr Carl Prausnitz (aka CP Giles), recorded by Dr Claude Dolman on March 5, 1961, when Prausnitz was 85 years old. Dr Prausnitz reflected on the cholera epidemic of 1892, when 10,000 cases occurred in Hamburg, Germany, with more than 5,000 deaths. After this, the city of Hamburg appointed a young American-born doctor, William Phillips Dunbar, to head its hygiene department. Ten years later, after his medical training, Prausnitz became Dunbar’s assistant. Because both physicians experienced hay fever, they began studies on the disease. We started with application of pollen to our eyes, and nostrils and those of other hay fever patients. We knew nothing about prior work, so we had to go over the whole ground again. Very soon we found that practically only the pollen of graminaceous plants produced the hay fever symptoms. They produced them to whatever mucous membrane they were applied. They produced the same symptoms when rubbed into the scarified skin. When inhaled, they produced asthma and when pollen extract solution was injected under the skin, very severe generalized urticaria and asthma occurred. After I had done this first experiment on myself, Dunbar—much against my wish—insisted that I give him an injection of the same stuff. The result was almost fatal because, remember, in those days we had no adrenalin. We had no cromolyn. I just stood helpless at his side until at length he recovered. Dunbar thought at the time that the pollen must contain a toxin and so we set about making an antitoxin by injecting horses with gradually

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increasing doses. The serum of those horses was dried, finely powdered and applied with a fine brush to the conjuctival mucous membrane or sniffed up the nose. This substance, called pollentine, proved extremely helpful to a very large number of hay fever patients and it was used on a large scale for many years, until at last the turning come, and the patients began to complain that they could not apply the powder any more without getting a serious reaction. It turned out that they had now become, in addition to their allergy to hay fever, allergic to horse serum. So that concluded that part of our work. Before World War I, Prausnitz became head of the Hydrophobia Department of the Hygienic Institute at the University of Breslau, Germany. He describes the discovery for which he is most famous. A few years after the war, one of my collaborators in the Hygienic Institute in Breslau, Dr Ku¨stner, said to me that he was allergic to fish. Was I interested in the subject? I said, ‘‘Yes, very much indeed.’’ We did some preliminary experiments with fish extract on him which showed him to be extremely sensitive. In fact, if he had the slightest trace of fish, sometimes without knowing that he had done so, he within a few minutes got asthma, urticaria, vomiting and diarrhea. An interesting paper by Ramirez had just appeared. A man had developed asthma after contact with horse dander late in life. Ramirez found that this man had just been transfused with the blood of a man suffering from asthma after inhalation of horse dander. That seemed to me to be a most interesting experiment, but I did not wish to become permanently allergic to fish. So I decided to carry out an experiment by injecting intradermally to myself various dilutions of Ku¨stner’s serum, and the following day, to inject each of those places, as well as control places in my skin with fish extract. The result proved that allergy to fish could be transmitted from the allergic person by his serum to healthy, normal people. But it didn’t last; it was only a momentary, transitory, reaction.

Prausnitz and Ku¨stner phenomenon: The P-K reaction

Discovery Until the simple but clever experiment reported by Carl Prausnitz (1876-1963) and Heinz Ku¨stner (18971963) in 1921,1 neither an exact pathophysiologic mechanism nor the mediator responsible for evoking the hypersensitive immediate wheal-and-flare response had been elucidated. In their demonstration of blood serum transference of specific cutaneous reactivity were 2 unusual circumstances. First was Ku¨stner’s manifestation of clinical symptoms after eating fish, but only if cooked, and the development of a positive immediate skin test response to fish, but only if the extract had been preboiled. In the usual patterns of food sensitization, denaturation destroyed or diminished the antigenicity of a protein; in Ku¨stner’s case chemical alteration apparently created an allergenic fraction.* The second related to the nature of Ku¨stner’s systemic reaction to fish. Its immediate onset and constitutional symptoms, including respiratory tract involvement, resembled typical sensitization and acute constitutional shock in the guinea pig. But unlike the experimental animal phenomenon, Ku¨stner’s serum was found to be devoid of precipitating, complementbinding, or antigen-neutralizing anaphylactic antibody and lacked the ability to passively sensitize guinea

*Similar uncommon experiences involving processed foods were subsequently reported: Duke’s 1926 citation of a patient whose asthmatic reactions to peanuts occurred after eating only roasted and salted varieties,2 and Rowe’s 1931 observation on hypersensitiveness to cooked, but not raw, fruits.3

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pigs. Considering the possibility that Ku¨stner was affected by an anaphylactic variant, they designed and conducted an investigative experiment targeting homologous species tissue, human skin. Prausnitz’s arm served as the recipient site of an intracutaneously injected sample of Ku¨stner’s serum. The later injection of a minute quantity of boiled fish extract into the targeted skin site evoked a typical and immediate wheal-and-flare response. Because evidence that the result did not have anything to do with the test recipient’s own allergic state (Prausnitz had seasonal hay fever), they obtained identical results in repetition of the experiment with Ku¨stner’s serum transferred to healthy human test subjects. In considering the possibility of a cell-carried supersensitivity, they failed to transfer with a solution derived from a preparation of ground and scraped deep cutis and subcutis layers of skin. In other control subjects, attempted transfers with sera from donors who had positive skin test responses to horse serum and tuberculin were also negative. At the same time, Ku¨stner’s inability to accept passive transfer of rye grass pollen hypersensitivity from Prausnitz’s serum was puzzling. Putting the issue on a quantitative basis, they wondered whether success might have been possible if sera from more highly grass-sensitive donors had been available. The answer to that conundrum awaited later explanation. Within the next 4 years, confirming reports by other investigators substantiated the Prausnitz-Ku¨stner (PK) experiment to be a valid original discovery. In 1923, passive transfer of immediate wheal-and-flare skin test reactivity to horse serum was demonstrated by de Besche4 with sera from horse-sensitive asthmatic patients and from subjects with hay fever from grass pollen, and with sera from subjects with hay fever by

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