Dr. Max D. Cooper (USA) and Dr. Jacques Miller (Australia) are being awarded for their discovery of the dual nature of adaptive immunity across a wide variety of animal species, including humans. They characterized B and T lymphocyte lineages, which has greatly impacted the understanding of disease pathology and therapeutic development. Through Dr. Miller’s studies on thymus ablation and Dr. Cooper’s work inspired by apparent differences in clinical manifestations of primary immunodeficiencies, they have revealed that B lymphocytes are responsible for humoral immunity, or antibody production, and T lymphocytes are responsible for cellular immunity. Their pioneering work identified the cellular building blocks of the immune system, allowing for modern advancements such as anti-cancer drugs and anti-cytokine antibodies for the treatment of autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease.
Dr. Max Cooper (USA) is an Emory University School of Medicine Professor in the Department of Pathology and Laboratory Medicine in Atlanta, GA, and was President of CIS from 1994-1995. He is a renowned pediatrician with more than 50 years of experience in the study of immunology. Dr. Cooper is a member of the Emory Vaccine Center and is a Georgia Research Alliance Eminent Scholar in Developmental Immunology. Alongside Dr. Jacques Miller, Dr. Cooper is being awarded the 2018 Japan Prize in the category “Medical Science and Medicinal Science” for the discovery of the dual nature of adaptive immunity, which identified the cellular building blocks of the immune system as we understand it today.
“B and T lymphocytes”, the key players in adaptive immunity
Up until the early 1960s, when Dr. Cooper and Dr. Miller began their research, interest among researchers was concentrated on antibodies. The central concern of immunology in the first half of the twentieth century was “humoral immunity”, or immune phenomena involving antibodies.
In contrast to antibodies contained in the serum, or the liquid part of the blood, immune phenomena caused by lymphocytes contained in blood cells are called "cellular immunity". Since the 1940s, immune responses involving lymphocytes, separate from humoral immunity, gradually came to be better understood, and over time, facts suggesting the existence of two types of immunity were reported. However, not until Dr. Cooper and Dr. Miller reported their research results could the existence of the two types be confirmed and the cells involved identified.
T lymphocytes were being produced by the mysterious organ, "the thymus"
After studying at the University of Sydney Medical School, Dr. Jacques Miller went to London in 1958 and began studying the pathogenesis of lymphocytic leukemia in mice at the University of London. At the time, Dr. Miller was strongly influenced by the leading immunologists, Dr. Peter Medawar and his pupil, Dr. James Gowans. Through experiments on rats, they discovered that lymphocytes play an important role in the rejection of grafts.
Lymphocytic leukemia in mice, which Dr. Miller was studying, develops and spreads from the thymus due to viral infection.
Having hypothesized that the thymus is where virus multiplication takes place, Dr. Miller decided to remove the thymus gland of a newborn mouse and see if injecting a virus would cause leukemia to develop. The treated mouse grew unexpectedly weak, and dissection revealed a reduction in lymphocytes in the lymph nodes and spleen.
Next, Dr. Miller transplanted a skin graft to the same mouse to see if it would be rejected. He knew from Prof. Medawar and Gowans’ research that lymphocytes would normally cause the graft to be rejected. But to his surprise, Dr. Miller observed that the skin of a heterologous mouse was successfully engrafted on the mouse with its thymus removed.
Also, by marking the lymphocytes and observing their movement throughout the body, he confirmed that lymphocytes originate from the thymus, which was regarded as a mysterious organ at the time.
These experiments confirmed that the thymus is the organ that produces and delivers lymphocytes. When he reported this discovery in 1961, Dr. Miller named this lymphocyte the thymus-dependent lymphocyte, which later came to be known as the “T lymphocyte”, with the T taken from the word, thymus.
In addition, Dr. Miller discovered that there are two types of lymphocytes with different functions, and that the thymus-dependent lymphocytes (T lymphocytes) are not only involved in immune responses that reject skin grafts, but also play a role in supporting the function of myeloid-dependent lymphocytes (B lymphocytes) responsible for the production of antibodies.
Demonstrating the two types of immune systems using chickens
Dr. Max D. Cooper became a pediatrician after graduating from the Tulane University School of Medicine. From 1963, he conducted research at the University of Minnesota under Prof. Robert Good, a leading figure in immunology research. At the time, Dr. Cooper was fascinated by a report indicating the possibility that the bursa of Fabricius in chicken is involved in the production of antibodies. Follow-up studies by other researchers also suggested that the bursa of Fabricius is responsible for immune functions different to that of the thymus, but there was no conclusive evidence.
Meanwhile, Dr. Cooper, from his clinical experience as a pediatrician, found hints of the existence of the two types of immune systems. In a patient with a certain hereditary immunodeficiency disease, Dr. Cooper detected sufficient levels of antibodies despite an abnormal proliferation of herpesviruses. However, in the case of another hereditary immunodeficiency disease, the patient was highly resistant to viral infection although no antibody response could be observed. From these cases, Dr. Cooper hypothesized that there are two types of adaptive immunity: one in which antibodies are involved and one in which it is not.
To confirm the role of the bursa of Fabricius and the thymus, as well as the existence of the two types of adaptive immunity, Dr. Cooper conducted the following experiment.
Newborn chickens whose bursa of Fabricius or thymus had been removed were irradiated with X rays to destroy any cells that may have been created before hatching. Their immune functions were then examined in detail. The results showed that the chicken whose bursa of Fabricius had been removed had no antibodies, while the chicken whose thymus had been removed had lost the ability to reject skin grafts, just like the mouse with its thymus removed (see figure).
This experiment revealed that cells derived from the bursa of Fabricius are essential for antibody response, and that cells derived from the thymus are involved in the rejection of skin grafts. Thus, the existence of the B lymphocyte lineage responsible for humoral immunity and the T lymphocyte lineage responsible for cellular immunity was demonstrated. Cells in mice derived from the bursa of Fabricius came to be called “B lymphocytes” with the B taken from the word, bursa. Thereafter, Dr. Cooper and his colleagues revealed that in humans, B lymphocytes are produced in the bone marrow, whose initial is also B.
Dr. Cooper further extended his findings to other animals through his discovery that the basic mechanism of controlling adaptive immunity by the two lymphocyte lineages is widely preserved in vertebrates, from humans to jawless species such as the lamprey, thereby deepening our understanding of the evolution of adaptive immunity.
Epoch-making contributions to modern immunology and to the treatment of intractable diseases and cancer
Dr. Cooper and Dr. Miller’s accomplishments established the basic concepts underlying modern immunology and served as the driving force behind the significant advances in immunology that followed. In addition to major advances in the understanding of the pathology of numerous immune disorders including autoimmune diseases, allergies and chronic inflammatory diseases, their concepts have also been adapted into many new therapeutic and diagnostic drugs. More recently, there has been grown anticipation surrounding the substantial progress being made in new epoch-making cancer treatments that utilize antibodies and immune cells, such as antibody drugs, immune checkpoint inhibitors and genetically modified T-cell therapies. These developments are manifestations of the power of modern immunology, of which the foundation was laid by Dr. Cooper and Dr. Miller’s pioneering research, and their legacy will continue to widely benefit society into the future.
About the Japan Prize
The Japan Prize is awarded to scientists and researchers, regardless of nationality, who have made significant contributions to the progress of science and technology, as well as society, to further the peace and prosperity of mankind. While the prize encompasses all fields of science, two fields are designated for the Japan Prize each year. Since its inception in 1985, the Japan Prize Foundation has awarded the Japan Prize to 91 laureates from 13 countries. For additional details about the Japan Prize Foundation and its activities, please visit http://www.japanprize.jp/en.