Summary of Proposal
Host institution name

Osaka University

Head of host institution Kiyokazu Washida, Osaka University, President
Prospective center
director
Prospective
administrative director
Title of center projectCenter name

Project Summary

Research fields

Research objectives

Shizuo Akira, Osaka University, Professor (WPI IFReC)
Norio Furushiro, Osaka University, Professor (WPI IFReC)
Osaka University Immunology Frontier Research Center
Osaka University Immunology Frontier Research Center (IFReC)
The aim of this program is to unveil the whole picture of dynamic immune system by
employing a variety of imaging techniques to visualize the immune cells within live
animals. We will attempt to improve an imaging technology, which allows us to track the
dynamic behavior of immune cells and their communications more directly andunderstand how immune cells respond to non-self such as pathogens and cancers invivo. Based on these basic studies, we will seek to develop new strategies for diagnosis
and treatment of various diseases including infectious diseases, autoimmune diseases,
allergy and cancer.
Fields: Immunology and Bioengineering
Relevant fields: Biosciences, Precision and mechanical engineering
Importance: Research on the immune system, which deals with the host defense
mechanism against invading microbial pathogens, is important in treatment of various
diseases including infectious disease, allergy, inflammation, autoimmune disease, andimmunodeficiency, all of which are intimately associated with abnormality in the immune
response. Although numerous studies have focused on identifications of cells andfactors involved in the immune system, it still remains unclear how immune cells actuallyinteract each other in the in vivo immune organs in response to infections or inpathological conditions. Thus, it will be necessary to develop a new imaging technologythat tracks the immune response as well as a method to artificially control the immune
response in the future. In foreign countries, the incorporation of the imaging technology
into immunology research has already started. However, such movement is not seen in
Japan, and both fields are still isolated. The immunology in Japan, especially Osaka
University, is internationally acclaimed in its high quality of basic research. Therefore,
creating a research center for immunology in Osaka University in which domestic andoverseas researchers come together, and explore the in vivo imaging of the immune
system is imperative to establish not only an new field of basic science but also
overcome the above-mentioned diseases.
Development of an imaging technology for visualization of immune system in vivo and a
new method based on the imaging technology that controls immune system for thetreatment of immune diseases

Dr. Norio Furushiro, who is familiar with managements in English, will head theadministration department. The administration department will have three sections: theresearch management section consisting of 2-3 members with PhD degree, andaccounting section and general affairs section each consisting of a senior supervisor
with rich administrative experiences in the University, and several bilingual or
English-speaking full-time and part-time personnel. The research management section
deals with planning and logistics of scientific meetings sponsored by the ResearchCenter, public information and liaison, and issues relating to intellectual properties.
Outline of management Center management committee consisting of center director (Chairman), administrative
director, Principal Investigators will make mid-to-long term plan of the Center based on
advices by the International Advisory/Review Board. The center director, based onsuggestions by the center management committee, will make decisions on major issues
necessary for center’s managements, such as researchers’ salaries, appointment of new
researchers and administrative director.
The University president will approve the center director’s decisions on major issues
necessary for center’s managements.
Our center will have about 200 people, including investigators, reseachers and staffs by
Researchers and other the year of 2010. The number of Principal Investigators will be about 20.
List of the name of main PI: Shizuo Akira, Tadamitshu Kishimoto, Toshio Hirano,
center staffs
Masayuki Miyasaka, Hitoshi Kikutani, Taroh Kinoshita, Atsushi Kumanogoh, Kiyoshi
Takeda, Hisashi Arase, Shimon Sakaguchi, Takashi Saito, Tomohiro Kurosaki, Fritz

Melchers, Toshio Yanagida, Junji Seki, Yoshichika Yoshioka, Takashi Jin, Yutaka Hata
List of the name of satellite organizations and other partner institutions: RIKEN ResearchCenter for Allergy and Immunology, National Institutes of Health, Harvard University,
New York University, Stanford University, California Institute of Technology, University ofCalifornia San Francisco○ Research management section consisting of people with PhD degree will be set up in
the administration department. The research management section deals with planningand logistics of scientific meetings sponsored by the Research Center, public
information and liaison, and issues relating to intellectual properties. The
administration department also includes accounting section and general affairs section
each consisting of a senior supervisor with rich administrative experiences in the
University, and several bilingual or English-speaking full-time and part-time personnel.
These administration staffs will fully support researchers so that researchers do nothave to spend their time in paper work and other administrative functions.
○ Budget for equipments will be allocated to invite PIs from institutions outside Osaka
University. Budget for consumables and supplies will also be provided to PIs so thatthose PIs are able to start research at maximum efficiency without losing time. To
facilitate acquisition of competitive research grants from domestic funding sources, theresearch management section in the administration department will help PIs fromabroad in application.
Outline of research○ Postdocs will be hired through advertisement of positions on major journals, such asenvironment
Nature and Immunity, and their home pages.
○ Dr. Norio Furushiro, who is familiar with managements in English, will head theadministration department. The administration department will have three sections: theresearch management section, accounting section and general affairs section.
○ The center director will organize the International Advisory/Review Board consisting of
ten-odd renowned immunologists. The International Advisory/Review Board willconduct evaluation of research groups’ achievement every or every other year. The
center director will determine principal investigators’ salaries based on the evaluationby the International Advisory/Review Board.
○ The main research building (ten floors and 9,400 square m) will be constructed byMarch 2009 with University budget and external donation, and most of its space will be
used for the Research Center.
○ The Research Center will organize international research conferences once a year.
○ Based on advices and/or suggestions by the International Advisory/Review Board, thecenter director will set up research environment suitable for international researchers.
i) Criteria and methods to be used for evaluating the center’s global standing in thesubject field
The following points will be evaluated not only quantitatively by numbers of
publications, their citation and so on but also by external reviews of the reviewing
committee that consists of internationally leading scientists in the corresponding fields.
(a) Major contributions to main research areas: Are principal investigators of thiscenter leading and advancing main research areas as major players in thecorresponding fields? (b) Creation of new research areas: Are principal investigatorsof this center opening or creating new research areas in the corresponding fields? (c)Contribution to human life: Are there any accomplishments from this center, whichhave made great contributions to increases of quality of human life in various ways
such as developing therapeutic or diagnostic means of diseases?
ii) Results of current assessment made using said criteria and methods(a) Major contributions to main research areas: Principal investigators of this center
have been leading main research areas of the immunology field (Shizuo Akira inresearch of innate immunity; Shimon Sakaguchi in research of regulatory T cells;
Tadamitsu Kishimoto and Toshio Hirano in research of cytokines), which are obvious
Outline of indicators forfrom an enormous number of citations of their papers. Toshio Yanagida is also aevaluating a center’s
pioneer of the single molecule imaging. (b) Creation of new research areas: Principal
global standing
investigators of this center are currently opening new research areas (Takashi Saito in
the single molecule imaging analysis of immune responses; Hitoshi Kikutani andAtsushi Kumanogoh in immune regulation by semaphorins). (c) Contribution to human
life: Tadamitsu Kishimoto and his colleagues developed anti-IL-6 receptor therapy for
inflammatory diseases, which is highly expected for treatment of various
immunological diseases such as rheumatoid arthritis.
iii) Goals to be achieved through the project (at time of interim and final evaluations)
Goals at time of interim- To keep current levels and global standing of immunological research of this center.
- To further grow new research area that were opened by this center and make themmajor ones in the corresponding area.
- To establish technical and theoretical basis of intravital and noninvasive single cell
analysis of immune responses.
Goals at final evaluation- To establish the methodology of intravital and noninvasive single cell analysis of
immune responses.
- To combine the above methodology with basic immunological knowledge obtained（Host institution： Osaka university Title of Center Project：Immunology Frontier Research Center）

2

by conventional immunology research of this center and to present new paradigm forunderstanding the immune network.
Osaka University will provide support to meet the necesally expence, on top ofGrant-in-aid (about 15 -20 hundred million yen/year)and Reserch Grants for Principal
Investigators.
.
Note:
Securing research
Past record of competitive research grants for Principal Investigators
funding
2002: 6.76 million dollars or 811 million yen; 2003: 9.39 million dollars or 1.127 billion
yen; 2004: 9.48 million dollars or 1.137 billion yen; 2005: 9.20 million dollars or 1.104
billion yen；2006: 9.60 million dollars or 1.152 billion yen; Average 8.88 million dollars or
1.066 billion yen.
WPI will be the top priority in the mid-term strategic target and plan, and Osaka
University will give full support by implementing institutional reforms that are necessary
for formation of the WPI and improving the research systems.
(1) Osaka University will assist the WPI to perform every possible support for operation
and research activities of WPI. Osaka University will provide supports to the WPI
resources that would be either greater or equal to the WPI project grant.
(2) The WPI will be recognized as a department within the university. Osaka University
will provide the Center Director with the entitlement to manage and operate the WPI.
The Center Director is entitled to make decisions regarding substantive personnel
and budget allocation as are the Deans and Directors in other faculties in Osaka
University. An Administrative Director will support the Center Director and he will be
responsible for office management so that the Director’s decisions are kept to thebare essentials. Osaka University will support the Center Director’s research
environment.
(3) Osaka University will support resource sharing/exchange between the WPI and otherdepartments.
(4) To maintain the excellent research environment for the WPI, the center will apply theexisting employment system of Osaka University, including the annual salarysystem. If the present employee system of Osaka University does not fit in with theSummary of hostoperation of the center, then Osaka University will consider revising andinstitution’s commitment
supplementing the present internal system of Osaka University. The new systemshould be flexibly operated. Osaka University will support the WPI's enforcement toendorse the system and its operation.
(5) A new research building of ten floors with 9400m2 of space will be constructed byMarch 2009 for the Research Center. Osaka University will also provide laboratory
space on the campus to accommodate research groups, which will join the ResearchCenter before the new research building is completed. To meet the spacerequirements for an animal facility for newly coming research groups, Osaka
University will construct a new block of animal facilities and provide it for the
Research Center’s use.
(6) Osaka University will start a new "one stop service office" for international
researchers and students in 2007. This all-in-one service aims to improve both theresearch and living conditions for visitors from abroad. Information including the
research and daily life on campus and in the surrounding area has already beenreleased on the web information service site “GCN-Osaka & Worldwide”. Osaka
University has established three Overseas liaison offices for Education andResearch. Their central task is to collect and transmit information, and scout highly
talented researchers. All the faculties and overseas offices of Osaka University willassist the WPI so as to become the “World Premier International Research Center”.

（Host institution： Osaka university Title of Center Project：Immunology Frontier Research Center）

3

Research Center Project
Host institution name

Osaka University

Head of host institution

Kiyokazu Washida, President

Title of center project

Osaka University Immunology Frontier Research Center

Center name

Osaka University Immunology Frontier Research Center (IFReC)
・ Briefly describe the general plan of the project.

The aim of this program is to unveil the whole picture of dynamic immune
system by employing a variety of imaging techniques to visualize theimmune cells within live animals. We will attempt to improve an imaging
technology, which allows us to track the dynamic behavior of immune cells
and their communications more directly and understand how immune cells
respond to non-self such as pathogens and cancers in vivo. Based onthese basic studies, we will seek to develop new strategies for diagnosis
and treatment of various diseases including infectious diseases,
autoimmune diseases, allergy and cancer. To this end, we will invite 10-20
world-class principal investigators to Osaka University Immunology Frontier
Research Center as core scientists in the project and expand by forming alinkage with domestic and overseas institutions that will function as
satellites.
・ Include a chart that illustrates the center’s overall structure including its collaborative
linkages with other domestic and foreign institutions, its system of external evaluation,and its management framework

Project summary

Osaka University Immunology Frontier Research Center
Director
Shizuo Akira

External
evaluation

Center management
committee
Core research group leaders

Research director
Shizuo Akira

Core researchgroupsImmunology (10-15 groups)
Imaging (3-5 groups)

Collaborative
linkages

Satellit
e
RIKEN
RCAI,
NIH, Caltech,
NYU, Stanford,
USCF, etc

International
advisory review
board

Administrative
director

Administrative
office(1) Research fields
・ Fill in the name of the research field of the project.

Immunology and Bioengineering
・ Choose relevant fields from among ①－⑦ below, specifying the inter disciplinary field(s) that the projectaddresses.

Biosciences, Precision and mechanical engineering(Osaka University Immunology Frontier Research Center)- 1 -①Biosciences, ②Chemistry, ③Material sciences, ④Electronics engineering and information sciences,⑤Precision and mechanical engineering, ⑥Physics, ⑦Mathematics
・Describe the importance of the proposed research, including domestic and international R&D trends in the field andJapan’s advantages.

The research on immune system, which is the host defense mechanism against invading microbial
pathogens, is therapeutically important with regards to treat various diseases (infectious disease, allergy,
inflammation, autoimmune disease, and immunodeficiency, etc.) in which the immune system takes part.
Although numerous studies have focused on identifications of cells and factors involved in the immune
system, it still remains unclear how immune cells are actually changed in response to infections or inpathological conditions in vivo. Thus, it will be necessary to develop a new imaging technology that tracks
immune responses as well as a method to artificially control the immune response in the future. In foreigncountries, the uniting type of research on immunology and the imaging technology has already started.
However, both fields are still isolated and it has not become uniting in Japan. The basic research on
immunology in Japan, especially Osaka University, is internationally in a very high level. Therefore,
creating a research center for immunology in Osaka University in which domestic and overseas
researchers gather that aims to image the immune system in vivo is important to establish not only an new
field of basic science but also overcome the above-mentioned diseases.
・If centers in similar fields already exist in Japan or overseas, please list them.
Basel Institute for Immunology, Basel, Switzerland (1971-2001)(2) Research objectives
・Describe in a clear and easy-to-understand manner the research objectives that the project seeks to achieve by theend of the grant period (in 10 years). In describing the objectives, the following should be articulated in an easily
understandable manner: What new domains are expected to be pioneered by fusing the target fields. In theprocess, what world-level scientific issues are sought to be resolved. What is the expected impact of the scientificadvances to be achieved on society in the future.

○Explore the technology of in vivo imaging of immune system.
We aim to develop a new technology for visualization of immune cells in vivo through the merging of thetwo fields of immunology and bioengineering. This technology will provide us to understand the dynamics
of immune system in normal and pathological conditions. New findings obtained through imaging of theimmune reaction will lead to development of new strategies for diagnosis and treatment for various
immune diseases including autoimmune diseases, immunodeficiency, allergy and inflammation as well as
for development of vaccines for pathogens and tumors.
・Describe concretely the research plan to achieve the objectives, and any related past achievements by the hostinstitution.

We will attempt to develop a new technology that can visualize the dynamics of immune system at the levelof one living cell. To this end, we will extensively invite world-class researchers in the fields of immunology
and imaging. Through mutual interactions of both fields of researchers, we will attempt to design newprobes suitable for MRI and multi-photon microscopy that can track one immune cell in vivo. We will apply
those probes to visualize how immune cells respond to antigens and how immune cells behave in thepathological conditions like autoimmune diseases, allergy and inflammation. Based on the knowledge
which we will obtain with this system, we will establish a new paradigm of in vivo immune response andapply the new theory for treatments of immune-related diseases. Notably, Osaka University is famous for
immunology, especially innate and adaptive immunity and cytokine network that have been originallydiscovered by and extensively studied in this university. Osaka University has also conducted a world-topclass research in the field of engineering. This is a merit to perform a collaborative work between
immunologists and engineers as well as to invite researchers domestic and from overseas. Moreover,
Osaka University has an MRI/NMR system (11.7T) with a high resolution that is rarely housed in otherlaboratories of Japan, which is indispensable for achieving our project.

(Osaka University Immunology Frontier Research Center- 2 -(3) Managementi) Prospective center director
・ Fill in the name of the prospective center director, his/her age (as of 1 October 2007), current affiliation and position
title, and specialties. Describe his/her qualifications to be the center director.

Name; Shizuo Akira
Age; 54
Affiliation and title; Professor, Immunology Frontier Research Center, Osaka University
Specialties; Immunology
Qualifications; Professor Shizuo Akira has been obtaining several big grants in Japan, including
CREST, ERATO and 21 century COE, and he, as a project leader of these grants, has
successively published so many papers concerning innate immunity with high citation. Thesefindings clearly demonstrate that he has an ability to manage and organize a big grant program.
Moreover, the fact that he has obtained several international awards and topped a list of highly
cited researchers in the field of Immunology is attractive to many domestic and foreign
researchers involved in immunology research as well as in the imaging research, and will makethem participate in the establishment of this world-premier immunology center as principal
investigators and satellite researchers.
・ Attach a biographical sketch of the prospective center director using Appendix 2.
・ How does the prospective center director intend to construct the center and what is his/her vision of objectives to beachieved? Provide a synopsis written by the prospective center director (free format).
・ If possible, attach a letter (s) of recommendation for the prospective center director from researchers withworld-standard achievements in the subject field.
ii) Prospective administrative director
・Fill in the name of the prospective administrative director, his/her age (as of 1 October 2007), current affiliation andposition title. Describe his/her qualifications to be the administrative director.

Name: Norio Furushiro
Age: 63
Affiliation: International Student Center, Osaka University
Position title: Director and Professor
Qualifications: Dr. Norio Furushiro, the Director of the International Student Center and Professor of Osaka
University, is familiar with managements in English, and organization and administration system of
Osaka University.
・Attach a CV of the prospective administrative director (free format).

iii) Composition of administrative staff
・Concretely describe how the administrative staff is organized.

Dr. Norio Furushiro, who is familiar with managements in English, will head the administration department.
The administration department will have three sections: the research management section consisting of
2-3 members with PhD degree, and accounting section and general affairs section each consisting of twosenior supervisors with rich administrative experiences in the University, and several bilingual or
English-speaking full-time and part-time personnel. The research management section deals with planningand logistics of scientific meetings sponsored by the Research Center, public information and liaison, andissues relating to intellectual properties.

iv) Decision-making system
・Concretely describe the center’s decision-making system.

Center management committee consisting of director (Chairman), administrative director and a few
principal investigators will make mid-to-long term plan of the Center based on advices by the International
Advisory/Review Board. The director, based on suggestions by the center management committee, will
(Osaka University Immunology Frontier Research Center- 3 -make decisions on major issues necessary for center’s managements, such as researchers’ salaries,
appointment of new researchers and administrative director.

v) Allocation of authority between the center director and the host institution’s side
・Concretely describe how authority is allocated between the center director and the host institution’s side.

The University president will approve the mid-to-long term plan of the center and the center director’s
decisions on major issues necessary for center’s managements, such as researchers’ salaries,
appointment of new researchers and administrative director. The University president will makeappointment of director, determine the salary of director and make evaluation of the center’s performance.

(4) Researchers and other center staffsi) The “core” to be established within the host institutiona) Principal Investigators (full professors, associate professors or other researchers of comparable
standing)
numbers
Final goal

At beginning

At end of FY 2007

Researchers from within
the host institution
Foreign researchers invitedfrom abroad
Researchers invited from otherJapanese institutions

10

10

10

1

2

5

6

6

7

Total principal investigators

17

18

22

(Date: April, 2010)

・Describe the concrete plan to achieve final staffing goal, including steps and timetables.

(At the beginning)
Ten Professors from within Osaka University (Shizuo Akira, Tadamitsu Kishimoto, Toshio Hirano,
Masayuki Miyasaka, Hitoshi Kikutani, Taroh Kinoshita, Atsushi Kumanogoh, Kiyoshi Takeda, Hisashi
Arase and Toshio Yanagida) will set up and start the Research Center with Shizuo Akira as the director.
Two immunologists from RIKEN (Takashi Saito and Tomohiro Kurosaki) will join the center as
Professors. Prof. Melchers, as a part-time principal investigator, will start preparation to set up researchgroup while he will advise the director about organization of an international research center in
Immunology based on his enormous experiences in organizing Basel Institute for Immunology fortwenty years. Two members in imaging science (Yoshichika Yoshioka and Takashi Jin) will come to
Osaka University and set up labs in space provided by the University. Junji Seki and Yutaka Hata will
also join as a part-time principal investigator. Their labs will be located in the same building as
Yanagida’s lab and they will all together form “Imaging group”.
(At the beginning of FY 2009)
When the new main research building is completed, Prof. Shimon Sakaguchi will join.
(By the beginning of FY2010)
We will recruit two, preferably young, principal investigators from abroad through international
solicitation.
・Attach a list of principal investigators who are expected to join the center at the time of the application using
Appendix 1. Place an asterisk (*) by names of the investigators considered to be ranked among the world’s top
researchers. Describe the policy and strategy for inviting the rest of PIs who are to be invited in the future.

We plan to invite two principal investigators from abroad by April 2010. We will invite highly active young
investigators at Associate or Assistant Professor level. We will offer them full support including equipped
research laboratory and office, 3-4 post-doc positions, 2-3 support staffs and 5-year research fund. Our
strategy is to bring forth examples of foreign young principal investigators who are successful in research
operation in Japan, in turn, to attract more foreign investigators of high potential. We also plan to actively
recruit top-level researchers from abroad by providing higher salary and good research environment. While
investigators who are considered as top-quality researchers will be strongly supported by the center,(Osaka University Immunology Frontier Research Center- 4 -investigators whose evaluation by the international advisory review board is low have to leave the center.
This will increase the mobility of scientists as well as maintain and further upgrade scientific standards ofthe center.
・Attach a biographical sketch of each investigator using Appendix 2.
・As for the researchers invited from abroad or from other Japanese institutions, attach a letter of intent from eachof them to join the center project (free format).

b) Total members
Numbers

Researchers(Number of foreign researchersamong them and their percentage)
Principal investigators(Number of foreign researchersamong them and theirpercentage)
Other researchers(Number of foreign researchersamong them and theirpercentage)
Research support staffs
Administrative staffs
Total number of people who form
the “core” of the research center

Final goal

At beginning

At end of FY 2007

49
(12, 24%)

82(25, 30%)

147(47, 32%)

17(1, 6%)

18(2, 11%)

22(5, 23%)32(11, 34%)

64(23, 36%)

125(30, 34%)

28
9

34
15

44
15

86

131

206

(Date: April, 2010)

・Describe your concrete plan to achieve the final staffing goal, including steps and timetables.

(At the beginning)
Thirty or more researchers at levels of Assistant Professors and post-doctoral fellows, at least eleven ofthem being foreign researchers, will be hired in seventeen research groups. About 30 technicians andsecretaries will be hired and nine of 15 administrative staffs will be hired. In total, the Research Center
will be consisted of 86 or so members at the beginning.
(At the end of FY2007 or the beginning of FY2008)
The number of researchers at levels of Assistant Professors and post-doctoral fellows will be increased
to 50 or more. Among them 19 or more will be foreign researchers. We will also hire 10 graduate
students as Research Assistants (Four of them will be foreign students). The total number oftechnicians and secretaries will be increased to 34. The administrative department will become fully
staffed with 15 members. Total number of members in the Research Center will be 130 or so at the
beginning of FY2008.
(By the beginning of FY2010)
Three more principal investigators (one from Kyoto and two from abroad) will join the center by thistime. More researchers at levels of Assistant Professor and post-doctoral fellow will be hired for these
new research groups and other groups, and the total number of researchers at these levels will be
90-100. We will hire 20 more Research Assistants. Total number of support staffs will be 44. In total,
the center will have about 200 members. We will recruit highly capable non-Japanese scientists from
Asian countries as well as Japanese female scientists with high priority throughout the program.

ii) Collaboration with other institutions
・ If the “core” forms linkages with other institutions, domestic and/or foreign, by establishing satellite functions, fill in
the name of the partner institution(s), and describe the role of the satellite functions, personnel composition andstructure, and collaborative framework between the host institution and the said partner institutions (e.g., contracts tobe concluded, scheme for resource transfer).

Domestic(Osaka University Immunology Frontier Research Center- 5 -RIKEN Research Center for Allergy and Immunology
Overseas
NIH (Ronald Germain, Deputy Chief, Laboratory of Immunology and Chief, Lymphocyte Biology
Section, NIAID)
New York Univ. (Michael Dustin, Professor, Skirball Institute of Biomolecular Medicine)
California Institute of Technology (Scott Fraser, Director, Biological Imaging Center, Beckman Institute)
Harvard Medical School (Ulrich H. von Andrian, Professor, Department of Pathology)
Stanford University School of Medicine (Mark Davis, Professor, Department of Microbiology and
Immunology)
University of California San Francisco (Jason Cyster, Professor, Department of Microbiology and
Immunology)
The center will provide each satellite lab costs to hire several postdoctoral fellows. Researchers in thecenter and satellites will regularly visit each other and exchange the information to upgrade the scientificstandard in imaging. These interactions will provide an environment for the training of young
immunologists. We will attempt to have strong connections with various molecular imaging programs in
addition to these satellites, in which more innovative researches will be expected.
・If some of the principal investigators will be stationed at satellites, attach a list of these principal investigators and thename of their satellite organizations using Appendix 1, and provide a biographical sketch of each using Appendix 2.

Not applicable・If the “core” forms organic linkages with other institutions, domestic and/or foreign, without establishing satellite
functions, fill in the names of the partner institutions and describe their roles and linkages within the center project.

(５) Research Environment
・Concretely describe measures to be taken to satisfy each of the requirements outlined below, including steps andtimetables.

) Provide an environment in which researchers can devote themselves exclusively to theirresearch, by exempting them from other duties and providing them with adequate staff support tohandle paperwork and other administrative functions.
Research management section consisting of 2-3 members with PhD degree will be set up in theadministration department. The research management section deals with planning and logistics ofscientific meetings sponsored by the Research Center, public information and liaison, and issues relating
to intellectual properties. The administration department also includes accounting section and generalaffairs section each consisting of two senior supervisor with rich administrative experiences in the
University, several bilingual or English-speaking full-time and part-time personnel. These administration
staffs will fully support researchers so that researchers do not have to spend their time in paper work andother administrative functions.

ⅱ) Provide startup research funding as necessary to ensure that top-caliber researchers invited
to the center do not upon arrival lose momentum in vigorously pursuing their work out of concern
over the need to apply immediately for competitive grants.
Budget for equipments will be allocated to invite PIs from institutions outside Osaka University. Budget for
consumables and supplies will also be provided to PIs from abroad so that those PIs are able to startresearch at maximum efficiency without losing time. To facilitate acquisition of competitive research grants
from domestic funding sources, the research management section in the administration department will
help PIs from abroad in application.

ⅲ) As a rule, fill postdoctoral positions through open international solicitations.
Postdocs will be hired through advertisement of positions on major journals, such as Nature and Immunity,
and their home pages.

ⅳ) Establish English as the primary language for work-related communication, and appoint
administrative personnel who can facilitate the use of English in the work process.
Dr. Norio Furushiro, the Director of the International Student Center and Professor of Osaka University(Osaka University Immunology Frontier Research Center- 6 -who is familiar with managements in English, will head the administration department. The administration
department will have three sections: the research management section consisting of 2-3 members with
PhD degree, and accounting section and general affairs section each consisting of two senior supervisor
with rich administrative experiences in the University, several bilingual or English-speaking full-time andpart-time personnel.

ⅴ) Adopt a rigorous system for evaluating research and a system of merit-based compensation.
(For example, institute a merit-based annual salary system primarily for researchers from outside
the host institution. As a basic rule, the salaries of researchers who were already employed at thehost institution prior to the centers’ establishment are to be paid by the host institution.)
The director will organize the International Advisory Board consisting of ten-odd renowned immunologists.
The International Advisory Board will conduct evaluation of research groups’ performance every or every
other year. The director will determine principal investigators’ salaries based on the evaluation by theInternational Advisory Board.

ⅵ) Provide equipment and facilities, including laboratory space, appropriate to a top world-levelresearch center.
The main research building (ten floors and 9,600 square m) will be constructed by March 2009 with
University budget and external donation, and 80% of its space will be used for the Research Center. Aftermany of core research groups move into the new building, Osaka University will seek budget to renovate
the old building these research groups are currently using.

ⅶ) Hold international research conferences or symposiums regularly (at least once a year) tobring the world’s leading researchers together at the center.
The Research Center will organize international research conferences independently or in connection withthe annual Awaji International Forum on Infection and Immunity, which is organized since 2001 by the
Research Institute for Microbial Diseases, Osaka University. In this forum, we will often include abrainstorming session by inviting top scientists in other research areas, including genomics, physics andmathematics, which may provide unexpected new frontiers in immunology research. Especially, genomics
is an important component since genome-environment interaction appears to be linked to immunologicaldisorders.

ⅷ ) Other measures to ensure that top-caliber researchers from around the world can
comfortably devote themselves to their research in a competitive international environment, if any.
Based on advices and/or suggestions by the International Advisory Board, the director will set up research
environment suitable for international researchers.

(6) Indicators for evaluating a center’s global standing
・Describe concretely the following points.

i) Criteria and methods to be used for evaluating the center’s global standing in the subject field
The following points will be evaluated not only quantitatively by numbers of publications, their citationand so on but also by external reviews of the reviewing committee that consists of internationally leading
scientists in the corresponding fields.
(a) Major contributions to main research areas: Are principal investigators of this center leading andadvancing main research areas as major players in the corresponding fields?
(b) Creation of new research areas: Are principal investigators of this center opening or creating new
research areas in the corresponding fields?
(c) Contribution to human life: Are there any accomplishments from this center, which have made great
contributions to increases of quality of human life in various ways such as developing therapeutic or
diagnostic means of diseases?
ii) Results of current assessment made using said criteria and methods(a) Major contributions to main research areas:
Principal investigators of this center have been leading main research areas of the immunology field(Shizuo Akira in research of innate immunity; Shimon Sakaguchi in research of regulatory T cells;
Tadamitsu Kishimoto and Toshio Hirano in research of cytokines), which are obvious from an enormous(Osaka University Immunology Frontier Research Center- 7 -number of citations of their papers. Toshio Yanagida is also a pioneer of the single molecule imaging.
(b) Creation of new research areas:
Principal investigators of this center are currently opening new research areas (Takashi Saito in the
single molecule imaging analysis of immune responses; Hitoshi Kikutani and Atsushi Kumanogoh inimmune regulation by semaphorins).
(c) Contribution to human life:
Tadamitsu Kishimoto and his colleagues developed anti-IL-6 receptor therapy for inflammatory
diseases, which is highly expected for treatment of various immunological diseases such as rheumatoid
arthritis.
iii) Goals to be achieved through the project (at time of interim and final evaluations)
Goals at time of interim- To keep current levels and global standing of immunological research of this center.
- To further grow new research area that were opened by this center and make them major ones in thecorresponding area.
- To establish technical and theoretical basis of intravital and noninvasive single cell analysis of immune
responses.
Goals at final evaluation- To establish the methodology of intravital and noninvasive single cell analysis of immune responses.
- To combine the above methodology with basic immunological knowledge obtained by conventional
immunology research of this center and to present new paradigm for understanding the immune
network.

(7) Securing research fundingi) Past record
・Indicate the total amount of research funding (e.g., competitive funding) secured by principal investigators who will
join the center project. Itemize by fiscal year (FY2002-2006) taking into account the percentage of time each will
devote to research activities at the center vis-à-vis the total time they spend conducting research activities （“Effort②” in Appendix 2）. For example, if this percentage is 70%, then 70% of his/her research funds can be counted in
calculating the total amount of research funds.

Past record of competitive research grants for Principal Investigators
2002: 6.76 million dollars or 811 million yen; 2003: 9.39 million dollars or 1.127 billion yen; 2004: 9.48
million dollars or 1.137 billion yen; 2005: 9.20 million dollars or 1.104 billion yen；2006: 9.60 million dollars
or 1.152 billion yen; Average 8.88 million dollars or 1.066 billion yen.

ii) Prospects after establishment of the center・ Based on the past record, describe the concrete prospects for securing resources that match or exceed the
project grant.
・ Calculate the total amount of research funding (e.g., competitive funding) based on the percentage of time theresearchers devote to research activities at the center vis-à-vis the total time they spend conducting research
activities （“Effort ②” in Appendix 2）. Be sure the prospects are realistically based on the past record.

The specific measurements are as follows:
1) Indirect cost: 3.7 million dollars or 450 million yen.
2) Construction of main research building: 1.8 million dollars or 210 million yen.
3) Provision of other research space: 0.1 million dollars or 10 million yen.
4) Partial payment of Principal Investigators’ salaries: 1.3 million dollars or 150 million yen.
5) University budget for Principal Investigators: 0.3 million dollars or 40 million yen.
6) Competitive Research Grants for Principal Investigators: 8.7 million dollars or 1.05 billion yen.
7) Facilitation of external donations: 0.8 million dollars or 100 million yen.
Total: 16.7 million dollars or 2.01 billion yen.

Others・ Describe activities and initiatives to be taken after project funding ends.

After project funding ends and the project turns out to be successful, one possible initiative will be
integration of the Immunology Frontier Research Center and Osaka University International ResearchCenter for Infectious Diseases: the latter is a currently operating research center focusing on infectious
diseases and will function complementally with the proposed Immunology Frontier Research Center. Suchintegration will include reorganization of related departments in Osaka University and will lead to the next
(Osaka University Immunology Frontier Research Center- 8 -generation world premier international research center.
・ Describe expected ripple effects （e.g., how the proposed research center project will have trailblazing componentsthat can be referred to by other departments in the host institution and/or other research institutions whenattempting to build their own top world-level research centers）.

The Osaka University International Research Center for Infectious Diseases described above will beeventually reformed following the Immunology Frontier Research Center as a model of world-levelresearch centers.
・ Describe other important measures to be taken in creating a world premier international research center, if any.
・ If one or more of the projects applying for Global COE program have some connections with this research center
project, list the project title(s) , outline(s), group leader(s) and the relationship(s) with this project.

Project title: System Dynamics of Biological Function
Outline: this project is planned to develop imaging technology, to analyze dynamics of various biologicalnetworks, and to perform modeling and simulation of such networks.
Group leader: Toshio Yanagida
Relationship: Toshio Yanagida, a group leader, is also a principal member of this center project. Bothprojects focus on imaging technology and mutually interact each other.

(Osaka University Immunology Frontier Research Center- 9 -Center Director’s Vision

Osaka University Immunology
Frontier Research Center

Shizuo Akira, M.D., Ph.D
Director-1-1. Objectives to be achieved
The aim of this program is to unveil the whole picture of the dynamic immune
system by employing a variety of imaging techniques to visualize the immune cells
within live animals. We will attempt to improve the imaging technologies, which willallow us to track the dynamic behavior of immune cells and their communications more
directly and to understand how immune cells respond to non-self components, such as
pathogens and cancers, in vivo. Based on these basic studies, we will seek to develop
new strategies for the diagnosis and treatment of various diseases, including infectious
diseases, autoimmune diseases, allergies and cancers. To this end, we will invite 10-20
world-class principal investigators to the Osaka University Immunology Frontier
Research Center as core scientists in the project and expand the program by forming
links with domestic and overseas institutions that will function as satellites.
2. Background
Immunology is a medical science that investigates the mechanisms of the hostdefenses that protect the body against microbial infection (1). Although the immune
system is essential for eliminating infectious pathogens from the host, malfunction ofthis system gives rise to various immunological disorders, such as autoimmune diseases,
allograft rejection and allergic responses. Effective immune responses to pathogens andprotective immunity against reinfection with the same pathogen are generated through acomplex immune network exerted by various types of immune cells, including T
lymphocytes, B lymphocytes, dendritic cells, macrophages and natural killer (NK) cells.
These immune cells distinguish between self and non-self, and elicit integrated hostdefense responses as a system to efficiently eliminate invading pathogens. The
fundamental characteristics of the mammalian immune system are the motility andmigratory behavior of immune cells, which are originally derived from bone marrowcells. Immune cells leave the bone marrow and circulate in the blood. Subsequently,
some of these cells enter lymphoid organs, such as the thymus and lymph nodes, andsome re-enter the blood and move to tissues or organs throughout the body. The cell-cellinteractions among different immune cells are also important for immune responses. In
particular, cells of the innate and adaptive immune systems communicate extensively inthe lymphoid organs, and the communication between the cells determines the overall
immune responses in the body. The activities of these immune cells are also influenced
by non-immune cells, including fibroblasts, epithelial cells and endothelial cells.
To date, research in the immunology field has either been carried out by
isolating immune cells from the body and examining the cells in vitro or by using in-2-

vitro cultured cell lines. Although such studies have provided many new insights into
different immunology fields, we are still unable to draw the whole picture of
immunological responses or predict the outcome of immune responses when a certain
pathogen invades the body. Recently, in order to circumvent such drawbacks, webecame aware of the necessity to study such immune responses in a spatiotemporalmanner. Given the importance of the spatiotemporal organization of lymphoid organs in
the establishment of immune reactions, as well as the importance of analyzing immune
cell activation at the single cell level, immune cell and molecular imaging techniques
are vital for future developments in immunology research.
The imaging techniques for visualizing the immune system are still in the earlystages of development. To extend our understanding of the functions of the immune
system in vivo, new technologies are needed to examine cells and molecules that are
more deeply located in tissues, fainter and smaller, as well as to clarify the biochemical
events that occur on a very rapid timescale. The ability to simultaneously monitor an
increasing number of cell types and tissue structures is the key to developing a robust
understanding of how tissue organization, extracellular factors and cell movements
combine to support the development of useful immune responses. In order to overcome
such imaging challenges, interdisciplinary efforts in physics, computer science andimmunology are required. Despite such hurdles, the imaging techniques have rapidly
been applied to the immunology field worldwide, particularly in the United States. In
fact, a conference named “Imaging Immune Responses” was held during this year’s
Keystone Symposia. Currently, immunology research in Japan is very strong. We havemade great contributions to the progression of immunology research, which are highly
appreciated worldwide. However, we have to admit that our imaging of the immune
system is behind that of the United States. The next 10 years of development in the
immunology field definitely relies on whether or not we can gain priority in imaging of
the immune system in vivo. To sustain the international domination of immunology inJapan, I propose to establish a new Immunology Research Center in which
immunologists can study the immune system by utilizing in vivo imaging techniques,and produce further innovations in bio-imaging for immunology research throughinteractions with researchers who are engaged in the development of imaging systems.
By integrating the immunology and imaging fields, we will be able to understand the
dynamic interactions of immune cells and their activation. This will allow us tomanipulate the immune system, leading to the development of vaccines for infectious
diseases based on novel strategies, concepts for immune therapies for various infectious
diseases and cancers, and methods for treating autoimmune diseases.

-3-3. Members and groups participating in the research center
Japanese immunologists have accomplished tremendous contributions to thedevelopment of modern immunology. In particular, Osaka University has won
worldwide acclaim for its outstanding achievements. The late Yuichi Yamamura, theformer President of Osaka University, initiated cancer immunotherapy using bacterial
extracts in Japan, and became a founder of the Japanese Society for Immunology.
Among the outstanding immunologists who have studied under Dr. Yamamura,
Tadamitsu Kishimoto has become an internationally acclaimed specialist in cytokine
research through his discovery of interleukin (IL)-6. Researchers disciplined under thesupervision of Dr. Kishimoto have also made fine contributions to the field of
immunology. For example, Toshio Hirano studied IL-6 biology and its signaling, Shizuo
Akira revealed the mechanism of pathogen recognition by innate immunity (2) and
Hitoshi Kikutani clarified the role of the semaphorin family in immune responses.
Eminent immunologists of Osaka University will participate in the new center. The
researchers will include Shizuo Akira (as Director), Tadamitsu Kishimoto, Toshio
Hirano, Masayuki Miyasaka, Hitoshi Kikutani, Taroh Kinoshita, Atsushi Kumanogoh,
Kiyoshi Takeda and Hisashi Arase. In addition, Shimon Sakaguchi (Kyoto University),
Takashi Saito (RCAI) and Tomohiro Kurosaki (RCAI) will be invited to join the center.

-4-All of these researchers have made great contributions to a variety of fields inimmunology. In particular, Shimon Sakaguchi discovered regulatory T cells, which are
now a hot topic in immunology, and his joining will enhance our status as aworld-premier immunology center. Furthermore, Fritz Melchers will join the center as aprincipal investigator. He was a director of the Basel Institute for Immunology from1980-2001, and President of the International Union of Immunological Societies from1998-2001. He is now a senior research group leader at the Max Plank-Institute for
Infection Biology (Berlin, Germany). I believe his joining will definitely strengthen theinternational prestige of the center.
Toshio Yanagida is renowned for single-molecule imaging in individual cells.
Furthermore, he recently set up the High Performance Bioimaging Research Facility inOsaka University, which houses an 11.7 Tesla magnet Magnetic Resonance Imaging(MRI) system. Junji Seki and Yoshichika Yoshioka are specialists in imaging techniques,
while Takeshi Jin and Yutaka Hata (University of Hyogo) are experts in developing
molecular probes for imaging and computational image processing, respectively.
In an attempt to promote bioimaging techniques in our center, we plan to set up
six satellites in foreign laboratories (all in the United States), which have made great
advances in bioimaging. These researchers will include: Mark Davis (Stanford
University), a specialist in single-cell imaging; Ronald Germain (NIH), Michael Dustin(New York University), Jason Cyster (UCSF) and Ulrich H. von Andrian (Harvard
University), experts in intravital two-photon imaging; and Scott Fraser (California
Institute of Technology), a specialist in MRI.
4. Planned activities of the center
4.1. Generation of immuno-imaging core facilities
Immune responses against pathogens within the body proceed as follows: 1)
pathogen recognition by innate and adaptive immune cells, and subsequent activation ofthese cells; 2) communication between immune cells and their maturation in lymphoidorgans, such as the lymph nodes and spleen; and 3) systemic and local immune
responses. For imaging of the immune reactions in each step, it is necessary to apply
appropriate and different techniques. The imaging techniques now being utilized in the
immunology field is composed of three parts.
First, single-molecule imaging is used for visualizing the activation of
intracellular signaling cascades in a single cell. Second, confocal and multiphoton
microscopy techniques combined with surgical methods have recently enabled dynamic
imaging of immune cells in situ. Third, various techniques, including positron emission-5-

tomography (PET), MRI, computer tomography (CT) and luminescence imaging, canpossibly be applied to the visualization of immune reactions in vivo in a non-invasive
manner, although these technologies still require improvement in terms of their spatial
and temporal resolutions. I will establish immuno-imaging core facilities in the newresearch building and utilize the High Performance Bioimaging Research Facility inOsaka University housing the 11.7 Tesla magnet MRI system. In the immuno-imaging
core facilities, we will attempt to develop novel techniques for the imaging of immune
responses in a single cell, in situ intravitally and in vivo in a non-invasive manner.
Furthermore, these techniques will be applied to research in the immunology field bytight collaboration between the imaging groups and immunology groups.
4.1.1. Single-molecule imaging
Single-molecule imaging is a technique for visualizing fluorescently-labeled
single molecules by fluorescence microscopy, mostly in living cells. High-sensitivity
video microscopy has allowed us to monitor the behavior of multiple fluorescentmolecules in individual cells. Furthermore, this technique provides information about
the structures of the molecules themselves, as well as the microstructures surrounding
the molecules. Intra- and inter-molecularfluorescent resonance energy transfer (FRET)
between single fluorescent molecules
provides information on the molecular
structure. Thus, this technique is useful for
visualizing signal transduction in immune
cells by monitoring the behavior of signaltransduction molecules. Considering theimportance of signaling cascade activation in
the responses to microbial infection andcytokines, broad application of thistechnology is vital for the future
development of immunology research.
Dr. Yanagida is a pioneer in thedevelopment of single-molecule imaging,and has established various techniques. His
TCR complexes in T cells.
group has succeeded in the direct detection
Yokosuka et al. Nat. Immunol. 6: 1253-1262, 2006of kinesin molecular motion, and alsovisualized epidermal growth factor (EGF)-EGF receptor complexes in living cells (3).
Visualization of microclusters formed by-6-Dr. Saito has succeeded in the imaging of T cell receptor (TCR) microclusters and their
behavior (4). In the proposed center, we will attempt to introduce these techniques in the
immunology field. Dr. Saito will continue his research in the imaging of TCR signalingat RCAI, and maintain close contact with Dr. Yanagida’s group in order to further
improve the single-molecule imaging technology. For this purpose, we will have asatellite in the group of Mark Davis, an expert in this field, to introduce state-of-the art
technology from his laboratory and exchange information regarding single-molecule
imaging.
4.1.2 Imaging of cellular behavior and interactions in situ
Immune cells, including lymphocytes and dendritic cells, communicate witheach other in response to infection with pathogens, and proper interactions of immune
cells are critical for the establishment of immune responses against pathogens. Immune
cells show a specific migratory behavior. After they leave the bone marrow, some cells
enter secondary lymphoid tissues, such as the spleen and lymph nodes, or the thymus.
The migration and trafficking of these cells are dynamically regulated. Furthermore,communication with T lymphocytes and stromal cells is critical for the properdifferentiation and maturation of T cells in the thymus. Although previous studies havebeen performed using static methods, the importance of dynamic analyses of theimmune system has been recognized.
Recent advances in theimaging of organs in situ, especially

An example of two-photon microscopy imaging.
Germain et al. Nat. Rev. Immunol. 6: 497-507, 2006

-7-

implemented in the United States,
have enabled us to visualize cellularbehavior and cell-cell interactions (5).
The application of confocal andmultiphoton fluorescence microscopy
instruments has been combined withnew surgical methods and techniques
for fluorescent labeling of cells. In
these imaging techniques, a cell typeof interest is labeled using
appropriate dyes or by expression offluorescent proteins and thenvisualized using confocal andtwo-photonormultiphoton

microscopy. In small animals like mice, explant or intravital imaging is now possible inseveral immune organs, such as the lymph nodes, bone marrow and spleen.
However, these techniques have not been extensively applied in Japan,
particularly in the field of immunology. We believe that this is due to the lack ofopportunities to fuse the immunology and imaging fields in Japan. Therefore, in ourcenter, I will create a research group that focuses on the imaging of immune cell
dynamics. The group will consist of a group leader and two postdoctoral fellows. This
group will work under the supervision of Dr. Saito, and intimately collaborate with theprincipal immunologists at the center. The group will be technically supported by Dr.
Yanagida as well as the overseas satellites, including the groups of Ronald N. Germain,
Michael Dustin, Jason Cyster and Ulrich von Andrian. A new facility equipped withmultiphoton fluorescence microscopes and related apparatus for imaging will beestablished in the new research building. In this facility, several trained technicians will
be hired to help with the imaging experiments carried out by immunologists.
4.1.3. Non-invasive monitoring of immune responses in vivo
Our ultimate goal is to develop
techniques
fornon-invasive
monitoring of the immune
reactions to various stimuli in vivo.
In order to understand dynamic
immune responses, it is necessary
to develop systems that effectively monitor how
pathogens invade and spread in the body and how
immune cells migrate and interact with each other in
response to invading pathogens. To these ends, weneed to improve the imaging techniques involving
luciferase imaging, CT and MRI.
The 11.7T MRI system at the High Performance
Luciferase imaging is currently the best
Bioimaging Research Facility, Osaka University
system for tracking the movement of(left). Sample imaging of a mouse head using thecells in the body, although the image
11.7T MRI (Brucker) (right).
resolution needs to be increased. The
new center will apply a luciferase
real-time in vivo imaging system to monitoring the immune responses after pathogen
infections in living mice. We will also use CT to monitor the inflammatory responses inmice. MRI is the most attractive technique for imaging of the immune system in the-8-whole body, although the spatiotemporal resolution needs to be greatly improved. Thisimaging technique is currently in its early stages, and is expected to make progress inthe near future through the development of new nanoprobes that can detect immune
cells and the generation of mice expressing a target protein for imaging (6). It is likelythat MRI technology will become an indispensable tool for basic research as well as
diagnosis. Dr. Yanagida will organize the imaging groups to make efforts toward
improving the MRI techniques to allow monitoring of the dynamics of individual
immune cells in live animals without invasion, through the use of the 11.7 T MRI
available in Osaka University and collaboration with Scott Fraser, one of the world's
leading experts in MRI.
4.1.4. Development of novel bioprobes
For successful immune cell imaging in vivo, excellent bioprobes need to be
newly developed. Commonly used fluorescent dyes have limitations regarding theirbrightness and stability. Quantum dots are one of the recently developed fluorospheresthat can potentially overcome these problems. Dr. Jin is an expert on quantum dots andwill work on the development of new bioprobes for fluorescence. Furthermore, novel
bioprobes for MRI detection urgently need to be developed.
4.1.5. Simulation and modeling
Data obtained by single-molecule imaging, multiphoton microscopy and MRI
analysis should be integrated to generate a model based on the characteristic behavior of
immune cells. However, given that dynamic 3D imaging data are so large, it isnecessary to develop bioinformatic approaches for integrating such data. Dr. Hata is anexpert in computing medical imaging data, such as MRI and CT. He will work withimmunology groups to develop novel systems for modeling immune responses. This
group will be technically supported by the group of Ronald N. Germain, an expert in thegeneration of models by applying systems biology approaches to the interpretation ofimaging data. Once a dynamic model has been generated, it will be verified by the
immunology groups with experimental approaches. Appropriate modeling will enable
us to simulate the immune responses to specific pathogens in silico.
4.2. Application of imaging techniques to studies of immunology
The new techniques developed in the imaging core laboratory and new
equipment introduced in the core facility will be applied by groups of immunology
researchers. Details of the projects to be worked on by these immunology research-9-groups are described below.
4.2.1. Imaging of innate immune responses
The innate immune system directly recognizes infected pathogens, and plays animportant role in the activation of adaptive immunity mediated by lymphocytes (2).
Toll-like receptors (TLRs) and cytoplasmic receptors, such as NOD-like receptors and
RIG-I-like receptors, are critical for the direct recognition of microbial components.
These receptors trigger specific signal transduction cascades in response to their ligands(microbial components), leading to the production of proinflammatory cytokines andtype I interferons. Dr. Akira’s group will utilize single-molecule imaging techniques tovisualize the behavior of the TLR molecules themselves, as well as TLR signaling
molecules. This project will allow us to understand the dynamic molecular interactionsof TLR signaling molecules. In addition, Dr. Akira will analyze the behavior ofcytokine- and interferon-producing cells in response to pathogen infections in lymphoidorgans and local infectious tissues using multiphoton microscopy. In addition, his groupwill maintain close contact with Dr. Yanagida’s group to establish an MRI technique for
imaging the time course of innate immune responses in vivo.
Dr. Takeda is a specialist in mucosal immunology, which maintains tolerance tononpathogenic antigens. His group will pursue the imaging of immune cells at mucosal
surfaces by generating reporter mice in order to monitor the regulatory functions ofmucosal immune cells and analyze them intravitally using multiphoton microscopy.
Dr. Arase is an expert in the biology of NK cells and their specific receptors.
His group will try to image the behavior of NK cells in response to viral infection using
multiphoton microscopy.
Dr. Kinoshita clarified an essential role of GPI-anchor in host cell protection
from autologous complement. To understand why GPI-anchored form of complement
regulatory proteins is important for the self-protection, his group will investigate
dynamic behaviors of complement proteins and GPI-anchored complement regulatory
proteins on the cell surface using imaging approach.
Dr. Hirano has identified that zinc functions as a second messenger in thesignaling pathway in dendritic cells. His group will attempt to visualize zinc behavior in
response to immune activation using MRI techniques.
4.2.2. Imaging of acquired immune responses
The cells involved in acquired immunity, namely T and B lymphocytes, possess
rearranged antigen receptors for recognizing invading pathogens. T and B cells with- 10 -

proper antigen receptors are activated and undergo maturation for rapid responses thateliminate reinfection with the same pathogen.
Dr. Saito has been working on the imaging of T cell receptor (TCR) and its
signaling molecules, and has revealed that the formation of TCR microclusters is a
critical step for T cell activation. His group will further pursue the imaging of TCR
signaling molecules using mouse genetics, and monitor T cell activation in situ by
multiphoton microscopy. He will also attempt to generate MRI techniques for in T cellscience.
Dr. Kurosaki is an expert in B cell signaling and immunology. His group will
work on imaging of B cell receptor (BCR) signaling by single-molecule imaging. In
addition, his group will analyze the B cell maturation process, known as the germinal
center reaction, by multiphoton microscopy.
Appropriate activation of lymphocytes is mediated not only by antigen
receptors, but also by signaling of co-stimulatory molecules. Drs. Kikutani andKumanogoh have worked on CD40 and semaphorin family members in the activation of
immune responses. Dr. Kumanogoh will investigate the roles of semaphorin family
members in immune cell interactions using multiphoton microscopy, while Dr. Kikutani
will analyze the effects of costimulatory molecules on lymphocyte trafficking in
response to viral infection.
Dr. Sakaguchi is renowned for the discovery of regulatory T cells and themechanism of immune suppression. Regulatory T cells play important roles inpreventing aberrant activation of immune responses. His group will work on imaging
the behavior of regulatory T cells as well as their interactions with other immune cells
using multiphoton microscopy and MRI techniques.
4.2.3. Imaging of immune cell trafficking
Multiphoton microscopy techniques have traditionally been used to monitor the
migration and trafficking of immune cells. However, the current techniques are notsufficient to clarify the reason why specific cell populations enter the secondary
lymphoid organs through the endothelium. Dr. Miyasaka will develop a technique formonitoring the endothelial changes that occur in specific venules or lymphatics during
leukocyte trafficking in real time. He will generate reporter mice to monitor the highendothelial venules and use these mice to visualize the endothelial transmigration of
immune cells.
4.2.4. Development of new technologies for the assessment of autoimmune diseases- 11 -

by imaging
Dr. Kishimoto discovered IL-6, an essential cytokine for inflammation, and has
clarified its importance in immune responses against infection and the development of
autoimmune diseases. He previously generated a monoclonal antibody that blocks the
IL-6 receptor, and this is now used to treat human autoimmune diseases, such as
rheumatoid arthritis and Newcastle disease. However, the molecular mechanism of theaction of this antibody is still under investigation. Dr. Kishimoto will apply luciferase
imaging and MRI techniques to elucidate the severity of experimental autoimmune
diseases, and will also establish new methods for evaluating such diseases.
4.3. Establishment of domestic and overseas satellites
In an attempt to promote bioimaging techniques in our new center, we will
have one domestic satellite and five satellites in foreign laboratories (all in the UnitedStates) that have made great advances in bioimaging.
First, we will have a satellite in RIKEN, RCAI (Yokohama). From this satellite,
Takashi Saito and Tomohiro Kurosaki will participate in the establishment of the centeras principal investigators. Dr. Kurosaki will move to Osaka University, while Dr. Saito
will maintain groups in both the RCAI and Osaka University. I believe that this satellite
is the key to the success of our research center, since many excellent researchers in theimaging field belong to RIKEN. For instance, Makio Tokunaga and Yasushi Seko areexperts in single-molecule imaging, and Atsushi Miyawaki is famous for developing
fluorescence molecules. Given that Dr. Saito is a core member for our research centerfor developing novel imaging techniques for immunology, I believe that he cancollaborate with these researchers in RIKEN toward fusing these two fields.
The overseas satellite members will include Mark Davis (Stanford University),
Ronald Germain (NIH), Michael Dustin (New York University), Jason Cyster (UCSF),
Ulrich H. von Andrian (Harvard University) and Scott Fraser (California Institute ofTechnology). The researchers allotted to these satellites will work under the supervisionof a chief investigator in each individual laboratory, and also exchange information on
in vivo imaging with the members of our imaging groups to help improve ourbioimaging techniques. The chief investigators and satellite researchers will regularly
visit our center for discussions and seminars.
I will organize an international symposium on bioimaging of the immune
system every year, at which the satellite leaders will present their updated findings. This
international symposium will enhance the mutual interactions among our center, RCAIand foreign satellites, and definitely make our center’s mission visible worldwide.

- 12 -

5. Recruitment of foreign researchers and organization of the international
symposium
I will organize an international symposium on bioimaging of the immune
system every year, which will definitely make our center’s mission visible worldwide.
I will set up two groups consisting of a foreign professor or associate professor
and several researchers working under their direction. These two principal researchers
will be selected by international public advertisements, and their research expenses will
be provided for 5 years from this grant.
In the new building, I will secure space for visiting scholars who will perform
short-term collaborative studies.
6. Summary
Finally, the main aims in this center are to promote the participation ofprincipal immunologists in imaging research, and encourage them to regularly utilize
such techniques in their own immunology research. I hope that new in vivo imaging
techniques developed in the center will be utilized worldwide, and that our center will
be recognized as one of the world-renowned immunology centers, particularly in
bio-imaging. Studies performed in this center will lead to the generation of novel
concepts for understanding the dynamics of immunology.
References
1.
Janeway, C., P. Travers, M. Walport, and M. Shlomchik. 2004. Immunobiology
6th Edition. Garland Science
2.
Akira, S., S. Uematsu, and O. Takeuchi. 2006. Pathogen recognition and innate
immunity. Cell 124:783-801.
3.
Sako, Y., S. Minoghchi, and T. Yanagida. 2000. Single-molecule imaging of
EGFR signalling on the surface of living cells. Nat Cell Biol 2:168-172.
4.
Yokosuka, T., K. Sakata-Sogawa, W. Kobayashi, M. Hiroshima, A.
Hashimoto-Tane, M. Tokunaga, M.L. Dustin, and T. Saito. 2005. Newly
generated T cell receptor microclusters initiate and sustain T cell activation by
recruitment of Zap70 and SLP-76. Nat Immunol 6:1253-1262.
5.
Germain, R.N., M.J. Miller, M.L. Dustin, and M.C. Nussenzweig. 2006.
Dynamic imaging of the immune system: progress, pitfalls and promise. Nat Rev
Immunol 6:497-507.
6.
Pautler, R.G., and S.E. Fraser. 2003. The year(s) of the contrast agent -- 13 -

micro-MRI in the new millennium. Curr Opin Immunol 15:385-392.

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Host Institution’s Commitment
Date September 2５, 2007
To MEXTName of host institution: Osaka University
Name and title of head of host institution: Kiyokazu Washida, President
Signature
I confirm that the measures listed below will be taken faithfully if “(project title)” is adopted under theWorld Premier International Research Center (WPI) Initiative.
＜Provision in host institution’s mid-to-long-term plan＞
・ Describe clearly the host institution’s mid-to-long-term strategy plan and how the center is positioned within thatstrategy.

Osaka University has from the start been committed to its mid-term strategic target as a university
emphasizing research, aiming to produce unique and high quality results at the forefront of research.
Notably, Osaka University is strongly focusing on “accomplishing high-level research results andplaying a crucial role in the establishment of the World Premier International Research Center (WPI)”.
Osaka University will further encourage the study of Advanced Science and Technology fields tomaintain its system of research practice.
The provisions of the mid-term strategic plan were set to accomplish the goals of the plan underthe existing implemented systems. If the proposal with Osaka University is selected as one of the“WPI” projects, the University will give the top priority to develop “Osaka University Immunology
Frontier Research Center” and subjoin in the mid-term strategic plan as effective measures to fulfill
the research quality and research results. In addition, Osaka University will support the WPI for
maintaining the research enforcement system. The WPI will be supplemented in the mid-term
strategic plan.
Osaka University in its mid-term organization planning (2004-2009) described and published that
one of the University’s specific targets is the establishment of the Research/Education Center of
Excellence in Microbiology and Immunology. The educational aspects of this planning is taking placethrough the 21st Century COE program entitled, “Combined program on Microbiology and
Immunology” (2003-2007). This 21st Century COE program will be followed by a new proposal to the
Global COE program. The research aspect of the planning consists of two parts. One focuses on
infectious diseases. Osaka University established the “Osaka University International ResearchCenter for Infectious Diseases” in 2005 including setting up the Research Collaboration Center on
Emerging and Reemerging Infections in Thailand as a branch. The other part of the research aspects
is to propose the “Osaka University Immunology Frontier Research Center” with its focus being
Immunology as the “World Premier International WPI (WPI) Initiative”. The two Centers will befunctionally complimentary. If the proposal with Osaka University is selected as one of the WPIInitiative projects, formation of the WPI will be the top priority in the mid-term strategic target and plan,
and Osaka University will give full support by implementing institutional reforms that are necessary forformation of the WPI and improving the research systems.
＜Concrete Measures＞
・Describe the concrete measures that the host institution will take to satisfy the following requirements.

(1) How it will support the center’s need to secure resources that match or exceed the project grantthrough such means as competitive grants obtained by researchers participating in the project,in-kind contributions and other forms of assistance by the host institution ( including partial
payment of salaries, provision of research space), and/or external donations.
Osaka University will assist the WPI to perform every possible support for operation and research
activities of WPI. Osaka University will provide support to the WPI resources that would be either
greater or equal to the WPI project grant.
The specific measures are as follows:（Host institution：Osaka University Title of Center Project：Osaka University Immunology Frontier Research Center）

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1) Indirect research expenses: 3.7 million dollars or 450 million yen.
2) Construction of main research building: 1.8 million dollars or 210 million yen.
3) Provision of other research space: 0.1 million dollars or 10 million yen.
4) Partial payment of principal investigators’ salaries: 1.3 million dollars or 150 million yen.
5) University budget for principal investigators: 0.3 million dollars or 40 million yen.
6) Competitive research grants for principal investigators: 8.7 million dollars or 1.05 billion yen.
7) Facilitation of external donations: 0.8 million dollars or 100 million yen.
Total: 16.7 million dollars or 2.01 billion yen for each year.
(2) How it will institute a system under which the center’s director is able to make substantive
personnel and budget allocation decisions necessary to implementing the center project—asystem, which in practice, allows the center director autonomy in making decisions regarding thecenter’s operation.
The WPI will be recognized as a department within the university. Osaka University will provide theCenter Director with the entitlement to manage and operate the WPI. The Center Director is entitled tomake decisions regarding substantive personnel and budget allocation as are the Deans and Directors
in other faculties in Osaka University.
An Administrative Director will support the Center Director and he will be responsible for officemanagement so that the Director’s decisions are kept to the bare essentials. Osaka University will
support the Center Director’s research environment.
(3)The support it will provide to the center director in coordinating with other departments within thehost institution when recruiting researchers for the center, while giving reasonable regard to theeducational and research activities of those departments.
When a researcher from a different department in Osaka University joins the WPI as a full time
researcher, Osaka University will support the replacement by indirect research expenses and/or otherexpenses. If a researcher at other departments in Osaka University is working concurrently at thecenter, he or she will be exempted from educational work. Osaka University will support resource
sharing/exchange between the WPI and other departments.
(4)Its flexibility in applying, revising, or supplementing the host institution’s internal systems asneeded for the center to effectively implement new management methods (e.g.,English-language
environment, merit-based pay, top-down decision making) unfettered by conventional modes ofoperation.
To maintain the excellent research environment for the WPI, the Center will apply the existing
employment system of Osaka University, including the annual salary system. If the present employee
system of Osaka University does not fit in with the operation of the Center, then Osaka University willconsider revising and supplementing the present internal system of Osaka University. The new systemshould be flexibly operated. Osaka University will support the WPI’s enforcement to endorse thesystem and its operation as follows:
・The WPI will ensure that the retirement allowance to be paid to the hired researcher is based on the
total years of service to the Center and other institutions.
・The Housing of International Visiting Professors will be arranged by WPI and there is no need to payneither the security deposit nor key money.
・To hire exceptional researchers, their salaries can be changed from the existing system dependingon his or her ability.
・High English ability administrative staff will be hired from both inside and outside the University. There
will be on-the-job training after their employment.
The aforementioned items will undergo examination as necessary by related departments of Osaka（Host institution：Osaka University Title of Center Project：Osaka University Immunology Frontier Research Center）

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University.

(5) Its accommodation of the center’s infrastructural requirements (for facilities, e.g., laboratory
space; equipment; land, etc.).
A new research building of ten floors with 9,600m² of space will be constructed by March 2009 for
the Research Center. Osaka University will also provide laboratory space on the campus toaccommodate research groups, which will join the Research Center before the new research building
is completed. After many of the core research groups move into the new building, Osaka University willseek funds to renovate the old building these research groups are currently using.
To meet the space requirements for an animal facility for newly coming research groups, Osaka
University will construct a new block of animal facilities and provide it for the Research Center’s use.
(6) Other types of assistance it will provide to give maximum support to the center in achieving its
concepts and objectives and becoming a world premier international research center in both nameand deed.
In addition to the above, Osaka University will start a new “one stop service office” for international
researchers and students in 2007. This all-in-one service aims to improve both the research and living
conditions for visitors from abroad. Information including the research and daily life on campus and in thesurrounding area has already been released on the web information service site “GCN-Osaka &Worldwide”. This “one stop service office” does not only function as an information center, but also aims to
reduce the burdens placed on international researchers and students related to immigration, by offering
substantial support services such as visa application on their behalf. Osaka University has established three
Overseas liaison offices for Education and Research in San Francisco (U.S.A), Groningen (TheNetherlands) and Bangkok (Thailand). Their central task is to collect and transmit information, and scout
highly talented researchers. All the faculties and overseas offices of Osaka University will assist the WPI so
as to become the “World Premier International Research Center”.

（Host institution：Osaka University Title of Center Project：Osaka University Immunology Frontier Research Center）

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List of Principal Investigators

Name

①

Shizuo Akira*②

Tadamitsu
Kishimoto*③

Toshio Hirano*④

MasayukiMiyasaka*

⑤

⑥

⑦

⑧

⑨

⑩

⑪

⑫

⑬

⑭

⑮

⑯

⑰

⑱

Current affiliation(organization, department) and specialties

Academic degree

Osaka University, Immunology Frontier Research Center, Laboratory of
Host Defence, Research Institute for Microbial Diseases, Department MD, PhD
of Host Defense (Immunology)
Osaka University, Graduate School of Frontier Biosciences, Laboratoryof Immune Regulation, Immunology Frontier Research Center,
MD, PhD
Laboratory of Immune Regulation (Immunology)
Osaka University, Graduate School of Frontier Biosciences, Graduate Schoolof Medicine, Laboratory of Developmental Immunology, RIKEN Research
MD, PhD
Center for Allergy and Immunology, Laboratory for Cytokine Signaling,
Immunology Frontier Research Center, Laboratory of Developmental

Osaka University, Graduate School of Medicine, Laboratory of
Immunodynamics, Immunology Frontier Research Center, Laboratory MD, PhD
of Immunodynamics (Immunology)
Osaka University, Research Institute for Microbial Diseases,
Hitoshi Kikutani* Department of Molecular Immunology, Immunology Frontier Research MD, PhD
Center, Laboratory of Molecular Immunology (Immunology)
Osaka University, Immunology Frontier Research Center, Laboratory of
PhD
Taroh Kinoshita* Immunoglycobiology, Research Institute for Microbial Diseases,
Department of Immunoregulation (Immunology, Biochemistry)
Osaka University, Immunology Frontier Research Center, Laboratory ofAtsushi
Immunopathology, Research Institute for Microbial Diseases,
MD, PhD
Kumanogoh
Department of Infectious Disease Pathology (Immunology)
Osaka University, Graduate School of Medicine, Laboratory of Immune
Kiyoshi Takeda Regulation, Immunology Frontier Research Center, Laboratory of
MD, PhD
Mucosal Immunology (Immunology)
Osaka University, Immunology Frontier Research Center, Laboratory of
Hisashi Arase
Immunochemistry, Research Institute for Microbial Diseases,
MD, PhD
Department of Immunochemistry (Immunology)
Kyoto University, Institute for Frontier Medical Sciences, Department of
ShimonExperimental Pathology, Immunology Frontier Research Center,
MD, PhD
Sakaguchi*
Laboratory of Experimental Immunology (Immunology)
RIKEN Research Center for Allergy and Immunology, Laboratory for
Takashi Saito*
Cell Signaling, Immunology Frontier Research Center, Laboratory of PhD
Cell Signaling (Immunology)
RIKEN Research Center for Allergy and Immunology,Laboratory for
Tomohiro
Lymphocyte Differentiation, Immunology Frontier Research Center,
MD, PhD
Kurosaki*
Laboratory of Lymphocyte Diffentiation (Immunology and molecular
Fritz Melchers*

Max Planck Institute for Infection Biology, Germany & University ofBasel, Biozentrum, Dept. of Cell Biology, Switzerland (Immunology)

PhD

Osaka University, Graduate School of Frontier Biosciences,
Toshio Yanagida* Laboratories for Nanobiology (Soft Biosystem Group), Immunology
PhD
Frontier Research Center, Laboratory of Single Molecule Imaging
National Cardiovascular Center Research Institute, Department ofJunji Seki
Biomedical Engineering (Biomechanics, Biorheology, Microcirculation), DSc
Immunology Frontier Research Center, Laboratory of Biomedical
Advanced Medical Science Center of Iwate Medical University, High
Yoshichika
Field Magnetic Resonance Imaging Research Institute (Biophysics),
DSc
Yoshioka
Immunology Frontier Research Center, Laboratory of Biofunctional
Hokkaido University, Research Institute for Electronic Science, Section
Takashi Jinof Intelligent Materials (Molecular Recognition Chemistry), ImmunologyDSc
Frontier Research Center, Laboratory of Nano-bio Materials (Imaging)
Division of Computer Engineering, Department of Electrical Engineeringand Computer Sciences, Graduate School of Engineering, University of
Yutaka Hata*
PhD
Hyogo (Computer Engineering), Immunology Frontier Research Center,
Laboratory of Information System (Imaging)

Osaka University Immunology Frontier Research Center