National Research Institute for Child Health & Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
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Dr. Kimishige Ishizaka (Fig. 1) passed peacefully away from heart failure at dawn of July 6, 2018 in Yamagata, Japan. Dr. Kimishige Ishizaka and Dr. Teruko Ishizaka (the Ishizakas; partners in marriage and in research) were best known for their discovery of immunoglobulin E (IgE) in 1966.1
Dr. Kimishige Ishizaka was born on December 3, 1925 in Tokyo. When he was a medical student, he spent his summer vacation in 1946 training in bacteriology with Professor Keizo Nakamura. He and Teruko met during the training course. He graduated from the University of Tokyo in 1948 and married Teruko in 1949. He received his PhD in 1954 from the University of Tokyo. Immediately afterward, Prof. Nakamura appointed Dr. Ishizaka as Chief of the Immunoserology Division of the Department of Serology at the Japanese National Institute of Health. During his tenure in that position (1954–1962), he spent two years as a Postdoctoral Research Fellow at California Institute of Technology in Pasadena, California in the United States (1957–1959) under the supervision of Professor Dan H. Campbell. At that time, Prof. Campbell hypothesized that formation of antigen–antibody complexes in vivo might be responsible for induction of anaphylaxis. He asked Dr. Ishizaka to verify this hypothesis. Although their direct association was only two years, Prof. Campbell's words and generosity seem to have left a lasting impression on Dr. Ishizaka. In this way, Dr. Ishizaka started his journey toward the discovery of IgE.2
At that time, Japan still had no funding system that supported young investigators like Dr. Ishizaka.2 In 1963, the Ishizakas joined the Children's Asthma Research Institute and Hospital in Denver, Colorado in the United States. Dr. Ishizaka was intrigued by the underlying mechanism of hay fever and the nature of so–called “reagin”, which was a yet–unidentified factor postulated as being responsible for Prausnitz–Küstner reactions in the sera of allergic patients. His initial thought was that the Fc portion of an immunoglobulin might determine its ability to induce anaphylaxis, and that characterization of “reagin” would verify this hypothesis. These ideas were not received favorably in the early ‘60s in Japan.
After struggling with this project for a few years in Denver, Dr. Ishizaka concluded that the amount of “reagin” contained in patients’ sera was too low to detect using the technology available at that time. They changed their approach from detecting “reagin” to producing anti-human reagin antibodies in experimental animals. After struggling again for a half year, the Ishizakas were able to generate anti-human reagin rabbit antibodies. Using the rabbit serum, “reagin” became visible as a new class of immunoglobulin at an electrophoretic position that was distinct from the immunoglobulin isotypes known at the time. Their approach was to obtain a semi-purified antibody by gel electrophoresis, and to then react it with isotope-labeled ragweed antigen (the patients who provided sera were allergic to ragweed).1, 2, 3 In this way, the Ishizakas discovered IgE in 1966. Thirteen years later a similar method, now called Western blot, was established as a standard method for identifying unknown proteins.4, 5 Some people remained skeptical and did not rule out the possibility that reagin and the Ishizakas' new antibody class were separate molecules that co–migrated.6 Then Dr. Gunnar Johansson, Dr. Hans Bennich and colleagues discovered a novel myeloma protein that had reagin activity and was bound by the Ishizakas’ antiserum.7 The discovery of IgE was officially recognized by WHO in 1968. Needless to say, the discovery of IgE is considered the biggest breakthrough in our understanding of allergy.1, 2, 4
The Ishizakas wanted to use the IgE myeloma protein to elucidate the mechanisms of allergy, but they could not obtain a sufficient amount of it. Then, in 1968, a second patient (Mr. Peter Shackford) with IgE myeloma was identified. In response to the Ishizakas’ passion for elucidating enigmatic allergic diseases, he generously provided more than 30 L of plasma by undergoing weekly plasmapheresis until his death for a half year. The Ishizakas (mainly Kimishige) isolated E myeloma protein (named PS) from his plasma. Since many allergists and immunologists were interested in the IgE system, the Ishizakas (mainly Teruko) sent purified PS protein and/or anti-PS antibodies to many investigators in the US and Europe upon request, including to investigators who had initially been skeptical of their findings. The number of such shipments of PS protein/anti-IgE to researchers during the next 10 years was close to 100. Thus, PS protein and antibodies to it greatly facilitated the progress of allergy research in the 1970s.1
In 1970, Dr. Kimishige Ishizaka was appointed O'Neill Professor of Medicine and Microbiology at Johns Hopkins University School of Medicine in Baltimore, Maryland. From 1981 to 1989, he served as Director of the Department of Immunology at the university. He became Scientific Director, and then President, in 1990, of the La Jolla Institute for Allergy and Immunology in La Jolla, California. He officially retired in 1996, primarily because of gradual worsening of Teruko's Parkinsonism symptoms. Dr. Ishizaka decided to dedicate the rest of his life to Teruko because he knew that she had dedicated all her life to him and their shared career until then. Indeed, Dr. Ishizaka wrote in his books that Teruko served as his wife, his housekeeper, his manager, his diplomat and his scientific partner, at considerable sacrifice of her own scientific career.
They returned to Teruko's hometown, Yamagata, in the northern part of Japan, where they built a new house. However, in 1998, her symptoms became much worse and she was hospitalized in Yamagata University Hospital after being diagnosed with degeneration of nigrostriatal neurons. He visited Teruko from 9 a.m. to 5 p.m., almost every day. In her hospital room, he wrote many articles and talked to and advised people in various fields for 20 years. At the time of his death, he was serving as Honorary Director of the Institute of Immunology at Yamagata University, and as President Emeritus of La Jolla Institute for Allergy and Immunology.
The Ishizakas received numerous awards for their achievements. In 1972, they received the Passano Foundation Award. In 1973, he received the German Paul Ehrlich and Ludwig Darmstaedter Prize, the Takeda Medical Award, and the first Scientific Achievement Award of the International Association of Allergology, and they together received the Gairdner Foundation International Award. In 1974, he received the Imperial Prize of the Japan Academy, and the Japanese Order of Culture. In 1979, they received the Borden Award. In 2000, he was awarded the 16th Japan Prize. Among the many prizes and plaques he received, his favorite was the plaque awarded to them in 1970 from Children's Asthma Research Institute and Hospital, on which the following phrase was inscribed: “As Physicians and Researchers, You Are Second to None; As Human Beings You Are the Finest”.
Dr. Ishizaka is renowned as having mentored many young investigators who later became outstanding scientists. They include the late Dr. Tomio Tada, who discovered a T cell subpopulation having immunosuppresive activity and had a second successful career as an author of traditional Noh stage plays8; Dr. Tadamitsu Kishimoto, who discovered IL-6; Dr. Kiyoshi Takatsu, who discovered IL-5; and Dr. Thomas Platts-Mills who first identified a dust mite allergen. As noted by Dr. Ishizaka, although the total number of postdoctoral fellows who had trained in their laboratories in the U.S. was only 50, 25 of them became professors in medical schools and/or heads of departments at prominent institutions in the United States, Japan and European countries.2 His mentorship and support of his trainees often continued even after they returned to their native countries, like Prof. Campbell supported Kimi even after he went back to Japan. Dr. Ishizaka used to avoid certain research plans in order not to compete with projects that his former research fellows had already initiated. His trainees (like Dr. Kishimoto) took the same approach toward their own students (like Dr. Shizuo Akira). The Ishizakas' scientific ‘family’ increased logarithmically in size and came to represent a majority of leaders in Japanese societies of immunology and allergy. And that influence has not been limited to Japan: the immediate-past President of the World Allergy Organization, Dr. Mario A. Sánchez Borges, of Venezuela, was a research fellow of Dr. Tada.
Just a month before his death, I talked with Dr. Ishizaka, my long-time mentor, on the phone about his recent review article.2 I complimented him on the content and quality of the paper. While thanking me, he said that Bill Paul (Dr. William E. Paul) died right after his review paper9 was published in the same journal, and that he was worried about a possible “jinx”. I replied that the association between Dr. Paul's publication and his death was merely a coincidence, comparable to a single case report. I said the evidence level of such an association seemed very low, and I would not believe it. While we laughed on the phone, at the same time, I felt uneasy since he had been coolly rational all his life and had never believed in concepts such as jinxes. But then his premonition came true. The nurse assured me that he died peacefully, as if he were falling asleep. I think that he was probably fully confident that even after his death, Teruko, an honorary citizen of Yamagata City, would be kindly cared for by the gentle staff of Yamagata University Hospital, who rightfully love and respect both Teruko and Kimishige Ishizaka.
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