Kimishige Ishizaka

Renowned immunologist and past AAI president Kimishige Ishizaka, M.D., Ph.D. (AAI ’58) died on July 6, 2018. Dr. Ishizaka, the 1984–1985 AAI president who served on the AAI Council from 1979 to 1986, was the long-time president and scientific director of the La Jolla Institute for Allergy and Immunology (LJI). The following remembrance was authored by Mitchell Kronenberg, Ph.D., (AAI ’84), LJI president and chief executive officer, and Gina Kirchweger, LJI chief communications officer. AAI gratefully acknowledges the submission.

Few scientific discoveries had the same immediate and profound impact on both basic science and the clinical understanding of a major group of diseases as the one described in a 1966 paper published in The Journal of Immunology. That paper, co-authored by Dr. Kimishige (“Kimi”) Ishizaka and his wife, Dr. Teruko (“Terry”) Ishizaka, unveiled a brand new antibody isotype, now known as immunoglobulin E (IgE), so named because it was originally detected in the serum of a ragweed-sensitive patient with antibodies to ragweed antigen E. Subsequent studies by Kimi, most of them co-authored with Terry, confirmed IgE as the critical mediator of allergies—and firmly established Ishizaka as a giant in his field. Dr. Kimi Ishizaka, who served as president of The American Association of Immunologists (1984–1985), died in Yamagata City, Japan, on July 6, 2018, at age 92.

Before the Ishizakas’ milestone paper, researchers had known that "reaginic factors" in the blood prompted reactions, such as erythema and wheal, when transferred with allergens from hypersensitive individuals. For more than 40 years, researchers tried to identify the molecules responsible for the response. They were unsuccessful, although evidence emerged from the Ishizakas and others that the Fc portion of Ig molecules could cause skin reactions when the Ig is cross-linked. Not afraid to experiment on himself, Ishizaka took advantage of newly developed analytical methods for serum protein fractionation and revealed the reaginic factor to be an allergen-specific Ig protein distinct from the previously characterized Igs that drive immune responses to pathogens, especially IgA, which, at one point, had been thought to contain reagin.

The novel isotype occurred in trace amounts in the γ-globulin fraction. Prevailing technologies, however, offered no means of purifying the isotype in large amounts, until a chance observation by Swedish scientists S.G.O. Johannson and Hans Bennich made the next step possible. They had isolated an unusual myeloma protein and realized that its properties were almost identical to those of γE, as described in the Ishizakas’ paper. The researchers decided to collaborate, exchanged reagents across the Atlantic, purified and characterized the still-mysterious γE, and positively identified it as a unique and novel Ig isotype.

What followed was a flurry of papers showing that IgE proteins elicited allergic responses by binding to mast cells, causing them to release histamine and other inflammatory factors that foment allergic responses, such as wheezing, rashes, or itching. Nowadays, routine blood tests, used to validate an allergic response, monitor the levels of IgE antibodies in response to a test stimulus.

After that discovery, Kimi, together with Terry, spent 25 years conducting immunology research into IgE molecular signaling and mast cell responses, first in Denver, where Kimi became chief of immunology of the Children's Asthma Research Institute and Hospital, and then on the faculty of the Johns Hopkins School of Medicine in Baltimore, where he led the immunology program. Over those years, Ishizaka himself published close to 200 papers and reviews relevant to the topic, most including Terry as co-author, indelibly linking his contributions to the steady progress of our understanding of allergies. All of it might not have happened but for an early twist of fate.

Born in 1925 in Tokyo, Ishizaka had envisioned a career as a practicing physician and entered medical school at the University of Tokyo in 1944. During a short summer stint in a bacteriology lab, his mentor, Professor Keizo Nakamura, asked him to translate an immunology book into Japanese, and young Kimi was smitten. After completing his medical training, he immersed himself in basic research and received a Ph.D. from the University of Tokyo.

In 1962, the Ishizakas, already partners in marriage and science, moved to the United States from Japan to conduct immunology research at the Children’s Asthma Research Institute and Hospital in Denver – he as assistant professor and she as research immunologist. Ishizaka had become interested in reagin and postulated that it was a type of antibody that would form a complex with the allergen and be responsible for the well-known erythema-wheal reaction in humans. At the time, there were no known seasonal allergy patients in Japan, prompting the Ishizakas to leave their home country to investigate possible mechanisms by using serum from hay fever patients. Within four years, they would publish their landmark paper on IgE and make history.

Impressed by their work, officials at Johns Hopkins School of Medicine recruited the Ishizakas to the newly established Immunology and Allergy Research Center, where they would spend the next two decades dissecting the molecular mechanisms driving allergic reactions. Thereafter, Kimi was courted by the Kirin Brewing Company management and local San Diego scientists, including Scripps Institute Director and former AAI President Dr. Frank Dixon, to lead the immunology research center that they were building on the Torrey Pines Mesa in La Jolla through its formative years.

At the La Jolla Institute for Allergy and Immunology (LJI), as it became known, Ishizaka assumed an administrative role as the founding scientific director in 1989 and two years later, added the role of president. He was particularly renowned for his generosity in guiding careers of young scientists whom he recruited there and for creating a warm, collaborative environment where colleagues felt like family.

Science, like any profession, can be ferociously competitive. To achieve scientific prestige and accomplishment and a high level of collegiality is not easy. Thus, Ishizaka's legacy as a leader is every bit as enduring as his work at the lab bench: "I believed that the best way to increase productivity was to encourage mutual communication between investigators by exchange of knowledge in their specialties," he once said. "We were very pleased that they helped rather than competed with each other."

Ishizaka won numerous scientific prizes for discovering IgE and related work. Among them were the 1972 Passano Award and the 1973 Gairdner Foundation International Award, both shared with Terry; election in 1983 to the National Academy of Sciences; the 1974 Order of Culture, which is the most prestigious scientific award in Japan; and the 1985 American College of Physicians Award for Achievement in Medical Science. After he retired, he won the 2000 Japan Prize from the Science and Technology Foundation of Japan for achievements in science and enhancing worldwide prosperity.

Throughout his scientific career in the United States, Ishizaka never forgot his origins and put enormous energy into training young investigators—many from Japan. In addition to those recruited to LJI, Kimi mentored several young immunologists in Denver and Baltimore who later became very prominent scientists. They include the following: Kiyoshi Takatsu, who discovered IL-5; Tadamitsu Kishimoto, who discovered IL-6; and (the late) Tomio Tada, who proposed a class of T cells with suppressor function and later became a Noh drama playwright.

Ishizaka's long career in the United States, commencing with his postdoctoral training at the California Institute of Technology in the late 1950s, came to a close when he returned to Japan in 1996, having retired as founding scientific director and president of LJI. He and Terry resided in Yamagata City, her hometown in northern Japan. At the time of his death, Kimi served as LJI president emeritus and as a director emeritus on the LJI Board of Directors.

Dr. Ishizaka is survived by Teruko, his wife of 68 years, and by their son Yutaka Ishizaka of Weston, Massachusetts.

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In addition to his service as a member and officer of the AAI Council, Dr. Ishizaka served as a member and chair of the AAI Awards Committee, chair of the AAI Nominating Committee, member of the AAI Program Committee, instructor on multiple occasions for the AAI Advanced Course in Immunology, and AAI representative on the Federation of American Societies for Experimental Biology Board.

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See also: Dr. Ishizaka's 2018 autobiographical essay, "The Way We Walked with Immunology," Annual Review of Immunology," 36: 1–18 (April 2018).

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