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Reinstalling Tissue Immune Tolerance and Homeostasis in Autoimmune and Inflammatory Diseases

Osaka University, Graduate School of Medicine, Professor

TAKEDA Kiyoshi

Purpose and Significance of the Research

Overcoming diseases caused by immune system abnormalities!

The immune system, which protects the human body from external pathogens, functions by regulating the balance between an activation mechanism, which serves as an accelerator, and a suppression mechanism, which serves as a brake. However, in recent years, a growing number of patients suffer from diseases caused by an abnormal immune state due to an imbalance between these opposing mechanisms, such as due to an overly active activation mechanism or weak suppression mechanism.
In this international joint research project, applied and interdisciplinary research using state-of-the-art technologies will be developed to elucidate the human immune mechanism. Furthermore, by restoring the balance between activation and suppression, we will develop innovative therapies for human autoimmune and inflammatory diseases that are currently difficult to treat.

Using state-of-the-art technologies to elucidate human immune mechanisms

Immune mechanisms have so far been elucidated in detail using mice. However, the human immune mechanism is not identical to that of mice. Human-derived samples need to be used in research to overcome human diseases, but conventional research technologies make it impossible to carry out analyses with the small amounts of samples provided by humans. The recent rapid progress in single-cell analysis using next-generation sequencing technology and informatics analysis technology has made it possible to carry out sufficient analysis even with these small amounts of human-derived samples. Therefore, research into the mechanisms underlying the human immune system and the development of therapies based on the research are now eagerly awaited. In this research, novel mechanisms will be elucidated by promoting interdisciplinary research such as imaging technology, and the development of treatments for human diseases will be strongly promoted using an international research network.

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Fig.1 Five programs to be conducted in this project

Organization of the Project Team

  • Kiyoshi Takeda(Osaka University)
  • Shimon Sakaguchi(Osaka University)
  • Tomohiro Kurosaki(Osaka University)
  • Masaru Ishii(Osaka University)
  • Kazuyo Moro(Osaka University)
  • Dylan Dodd (Stanford University, USA)
  • Ye Oo (University of Birmingham, UK)
  • Claudia Mauri (University College London, UK)
  • Marc Bajenoff (Université d’Aix-Marseille, France)
  • David Withers (University of Birmingham, UK)

Promoting collaborative research through an international research network comprising Japanese basic immunology researchers and overseas clinical immunology researchers.

The Japanese researchers are basic researchers belonging to the Osaka University Immunology Frontier Research Center (IFReC), which conducts basic immunology research at the world's highest levels mainly using cells and mice. The principal investigator, TAKEDA Kiyoshi, has made significant contributions to date in the field of immune regulation by gut bacteria and as IFReC’s Director leads collaborations with many international research organizations. The research group includes SAKAGUCHI Shimon, the discoverer of regulatory T cells and a world authority i-n this field; KUROSAKI Tomohiro, a pioneering researcher of memory B cells; ISHII Masaru, who discovered pathological bone-destroying cells using a novel imaging method; and MORO Kazuyo, who discovered innate lymphocytes and is contributing to the elucidation of their functions. On the other hand, the overseas researchers are clinical researchers with outstanding research achievements involving patients suffering from diseases caused by immune disorders, and microbiology or basic immunology researchers who are conducting research from a different perspective from the Japanese researchers.
In this interdisciplinary study, basic researchers receive patient-derived samples from clinical researchers and carry out detailed analyses that were previously impossible to carry out. The results of these analyses will be verified through experiments using mice and other means to clarify the human immune mechanisms involved in the disease, which will then be applied in clinical research.

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Fig. 2  International research network centered on IFReC at Osaka University that makes this research possible.

Plan for Fostering Early-career Researchers

On the Japanese side, 17 young researchers belonging to five teams that are globally recognized for their outstanding achievements in basic research will participate in the project. For these young researchers to lead the next generation of immunologists, it is necessary for them to broaden their research through direct contact with diverse ideas and technologies and to form their personal networks. To this end, since it is desirable for them to gain research experience abroad, they will be dispatched overseas on a long-term basis to collaborating research institutions. By acquiring the fields of expertise and technical know-how of the research institutes to which they belong both in Japan and overseas, they will develop as unique researchers and will give them a significant advantage in their career development.
The project will encourage the young researchers to implement their original research related to this research topic, allocate research funding for their research, and encourage and support the active acquisition of external funding. Meetings of research groups with young researchers will be held semi-annually, where young researchers will report on their research progress and will be mentored by senior researchers. Mentoring is also provided to postdoctoral researchers in particular from the perspective of research management to encourage their independence.
IFReC organizes the International School on Advanced Immunology to attract extremely talented young researchers. Extremely useful for building long-term personal networks of peers of the same generation, active participation of the young researchers in this project is encouraged. Outstanding young researchers will be recruited and fostered as IFReC provides them with travel support and promotes them to independent researchers.

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Fig. 3 International School on Advanced Immunology International School on Advanced Immunology, bringing together the world's best young researchers
Extremely useful for building a long-term personal network of young researchers of the same generation