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Research Area

Overview of Research Area

This research area aims to improve prevention, diagnosis, and treatment of human immunological diseases, centered on allergic and autoimmune diseases, and includes research for development of basic technologies for improvement of appropriate functioning of the immune system.
Diseases centered on allergic responses and autoimmune systems vary from those that may lower the quality of life (QOL) of patients to those leading to death in serious cases. Deepened understanding of the immune mechanism and control of such diseases at levels of molecules, cells, organs, and tissues will be evolved into understanding of a higher-level control immune network system at individual levels, leading to clinical application.
Specific examples of research projects include immunoregulatory mechanisms by regulatory cells, construction mechanisms of the mucous membrane immune system, autoimmune system, acquired immune system, and natural immune system and their control, etiological mechanisms of autoimmune and allergic diseases, immune and infection control mechanisms, development of drugs and vaccines against diseases and measurement of their effects, establishment of methods for diagnosis and treatment of diseases, and so forth.

Policy for Application collection, Screening and Research Area management by the Research Supervisor

Allergic diseases including pollinosis, which affect 10 and several percent of the population, and autoimmune diseases such as rheumatoid arthritis, many of which are considered to be intractable, are caused by excessive immune responses. Creation of innovative medical technologies addressing these immunological diseases is an urgent issue, and conventional basic research needs to move to clinical research and applications to this end.
In this area, researchers are expected to aim for development of medical technologies based on integrated utilization of activities of immunoregulatory cells, with a focus on the control of the whole immune response. One example is development of techniques for suitably controlling the amount and activity of immunoregulatory cells such as regulatory T cells, which have been found to have a function of keeping the overall balance of immune response normal and stable. In mucous membrane tissues, exposed to foreign antigens at all times, both the natural immune system and the acquired immune system are actively controlled and form a so-called mucous membrane immune system. Development of techniques for controlling this mucous membrane immune system and development of vaccines utilizing this system can be considered as other examples. Further, development of novel methods for diagnosis and treatment of autoimmune or allergic diseases targeting known or unknown immunoregulatory molecules is required.
For development of these techniques, basic research is essential, from conventional research at levels from molecules, cells, and tissues to those at individual levels. In this area, however, research from viewpoints of how the achievement is utilized to control the human immune system is particularly required. With this approach, we aim for elucidation of etiological mechanisms as well as innovative development of methods for diagnosis and treatment of human immunological diseases. In addition to diseases mentioned above, other examples include research that forms a technical basis for prevention, diagnosis, and treatment of many intractable diseases involving the immune system, such as cancer, infection, and graft rejection associated with organ transplantation, for example. Research proposals with an eye towards our own "Evolution of immune control therapy" are expected.

FY 2008, Strategic Sector

1. Title

Development of medical technology using immunoregulation to overcome allergic and autoimmune diseases including pollinosis

2. Content

This strategic sector aims to develop innovative medical technologies addressing diseases such as allergic diseases (e.g., pollinosis, an increasing nationwide health issue in Japan) and autoimmune diseases (e.g., rheumatoid arthritis) that are caused by excessive immune responses. The key element of the technologies is to control immunoregulatory cells (regulatory T-cells, etc.), which have been found to have functions to stabilize overall balance of the immune response. The technologies will form a scientific basis for prevention, diagnosis, and treatment of many intractable diseases (e.g., graft rejection associated with organ transplantation) as well as the diseases mentioned above. They can also contribute to reducing the national cost of medical care.

3. Policy position

This strategic sector corresponds to "Research for understanding higher-level control mechanisms, including,the immune system in living organisms" listed as a research and development theme within "Science and technology for reconstruction of complex systems of life" under "Strategic Prioritized Science and Technology." The research outcome will be used in "Translational research to clinical studies" to lead to another research and development theme under "Strategic Prioritized Science and Technology," called "Diagnostic methods and drug discovery for immune and allergic diseases."

4. Position of this research project among research promotion policies in relevant research fields, differences in content and political effectiveness from other related projects

Relevant measures include "Promotion of general research on immune and allergy" (RIKEN) and "Research on prevention and treatment of immune and allergic diseases" (Ministry of Health, Labor and Welfare). RIKEN conducts research on the elucidation of intracellular mechanisms and cellular response processes involved in the immune system and on the identification of the causes of diseases attributable to disturbances in the immune system. On the other hand, this strategic sector aims to develop medical technologies that control immunoregulatory cells from an integrated approach, focusing on regulation of overall immune response. Researchers in close association with clinical practitioners are currently working on the development of such medical technologies in universities around the country. To increase research efficiency, a research and development system that collaborate with not only RIKEN but also existing research institutions in universities such as affiliate hospitals will be developed in this strategic sector, with the aim of effective translational research.
In addition, effective immunotherapies are expected to be established by combining the achievements of this sector with various existing therapeutic methods associated with the immune system. Goals of this strategic sector and those of previous immunology researches by institutions including RIKEN are considered complementary.
The Ministry of Health, Labor and Welfare conducts researches that contribute to prevention, diagnosis, treatment, and other control measures of immune and allergic diseases mainly from a clinical standpoint, which differs from the research stage of this strategic sector.

5. Achievements and goals expected; and reasons, urgency, and need for priority from specialists and industries over other strategic priorities in science and technology

Allergic diseases, including pollinosis and autoimmune diseases, and many intractable diseases significantly lower the quality of life (QOL) and cause discomfort in many Japanese people. However, aggesive treatment tend to be avoided because the conditions are nonlethal and because of the availability (?) of non-radical palliative therapies. If this strategic sector can establish medical technologies that appropriately control the immune response, innovative treatment and preventive methods (e.g., vaccine against pollinosis) can be established.

1) Pollinosis affects at least 17 million (16%) Japanese (Nasal Allergy Medical Care Guideline, 2005) and the number of patients tends to increase annually. Allergic diseases, including food allergy and pollinosis, affect one third of Japanese (The Epidemiological Survey on Allergic Disease, 1992-1994). Allergic diseases affect people from infancy to adulthood. Although not life-threatening, a great burden in daily life exists because patients must avoid allergenic substances (e.g., selection of special school lunches for children with food allergy). Development of effective treatment is desired because few effective treatment methods are available.

2) About 5% of Japanese are affected by chronic autoimmune diseases (e.g., rheumatoid arthritis due to disruption of patients' own tissues by autoreactive lymphocyte, multiple sclerosis, autoimmune gastritis, and type I diabetes). Only palliative treatments that include immunosuppressive drugs are available, and these present problems of side effects including increased susceptibility to infection as well as heavy public financial burden due to the high drug cost.

3) Clinical studies of next-generation immunoregulatory therapies in which immunoregulatory cells suppress graft rejection associated with organ transplantation are about to be started in Germany and the U.S.A. In Japan, the importance of immunoregulatory cell function has been shown in the area of a liver transplantation from a living donor. The development of innovative medical technologies utilizing immune regulation is about to be realized in other fields.

Important diseases that need to be overcome in the 21st century, such as allergy and rheumatism, are targets of the "Strategic Priority for Science and Technology." Traditionally, research and development of prevention and treatment methods based primarily on the causes of those diseases have been promoted. In contrast, this strategic sector aims to develop technologies that utilize patients' own immunoregulatory function. The establishment of both of these technologies plays a complementary role; therefore, this strategic sector has high urgency and high social need.

6. Scientific justification for the research and development goals

As for immunoregulatory cells, it was shown in March 2007 that Foxp3, a protein specifically expressed in regulatory T-cells (an immunoregulatory cell type) suppresses T-cell function by directly binding to the transcription factors necessary for the function of T-cells (Nature, 2007). This result opened a path for the development of drugs that appropriately control the regulatory T-cell function by not only regulation at cell-level but also at molecular-level (inhibition or enhancement). This work was conducted by Japanese researchers.
As for applications to medical care, it was reported in the U.S.A. that tumor regression was frequently observed in patients after clonal repopulation with antitumor lymphocytes.
In Japan, the efficacy and safety of an immunotherapy utilizing regulatory T-cell function were confirmed in large animals last year. This immunotherapy successfully induced immune tolerance status in which the immune response to transplanted organs was specifically regulated and no rejection was observed without immunosuppressive drugs.
In general, immunology, including the research on immunoregulatory cells, is based on a clear and concrete theory and competitive research funds can effectively promote research in this field. For example, excellent research results, including the achievement mentioned above, were obtained through Grants-in-Aid for Scientific Research on Priority Areas, "The maintenance and disturbance of immune system homeostasis (2001-2005, Area representative, Shimon Sakaguchi, a Professor at Kyoto University)" and JST "Translational Research for Intractable Immune Disorders and Infectious Diseases (2001-2008, Research supervisor, Prof Tadamitsu Kishimoto, a Professor at Osaka University)" (completed or nearly completed). Special Coordination Funds for Promoting Science and Technology, "Molecular mechanisms of construction and action of the immune system and development of control technology for the mechanisms (2000-2005, Representative, Prof Kiyoshi Takatsu, a Professor at The Institute of Medical Science, The University of Tokyo)" nurtured young researchers. In view of these research outcomes, an environment that leads to new innovations from Japan, "Evolution of immune control therapy" is considered to have already been created.
As mentioned above, a lot of research results have been obtained on the elucidation of intracellular mechanisms and cellular response processes involved in the immune system and the elucidation of the causes of diseases attributable to a disturbance in the immune system. On the other hand, fewer researches have been conducted on the development of medical technologies aiming at clinical applications of new research findings. Therefore, it is necessary to intensively promote the translational reseaches in the future, in order to benefit the public.

7. Considerations in achieving the research and development goals

To achieve the goals of this strategic sector, universities should play a major role. In order to connect the results to innovation, it is important to communicate closely with researchers conducting other relevant researches in institutions such as RIKEN, as well as clinical research institutions. When good results are obtained, it is also important to rapidly move the project to the next phase (clinical research and research for business development) even during the research period of this project. In particular, it is expected that this strategic sector will extend far beyond basic research, because researchers in close association with clinical practitioners who are engaged in actual medical care will participate in this sector.
In addition, when excellent achievements are found, it will be necessary to establish the communication loop between the developmental and the basic research.

(Reference) Political goals to be achieved in this project

Examples of the basic technologies leading to the goals are given bellow. Their aims are to establish methods that appropriately control, from inside or outside the body, the amount and activity of immunoregulatory cells to enhance or suppress the immune response and to develop treatment methods for allergic diseases (e.g., pollinosis) and autoimmune diseases (e.g., rheumatism).

1) Development of drugs aiming to increase or decrease the amount of immunoregulatory cells and enhance or reduce their suppressive action

2) Development of treatment methods that utilize immunoregulatory cells, with a focus on immune response active tissues, such as mucous membranes

3) Development of pioneering new vaccines based on co-regulation of natural and acquired immunity