公益財団法人 セコム科学技術振興財団
研究成果報告書

研究課題名

健康長寿社会の実現に向けた新たな自己免疫制御療法の確立

Establishment of new anti-autoimmune therapy to facilitate a healthy long-lived society

研究期間
平成３０年１０月 ～ 令和４年９月

報告年月
令和 4 年 12 月
研究代表者
慶應義塾大学 薬学部 薬科学科 教授
長谷 耕二

Keio University Faculty of Pharmacy, Professor
Koji Hase Ph.D.

1

Abstract
In Japan, the population of the elderly aged 65 years or older is expected to reach about 40% by 2050 due tothe declining birthrate and aging society, and it is also predicted that the life expectancy will increase to 100 years
by 2050. With this shift to a society with a longer life expectancy, the number of patients with autoimmune diseases
such as rheumatoid arthritis and systemic lupus erythematosus is expected to increase. Among these, rheumatoid
arthritis, in particular, still affects approximately 700,000 people, and 15,000 people are newly identified as patients
every year. Chronic rheumatoid arthritis is characterized by the production of autoantibodies, including
rheumatoid factor, and the disease progresses by inflammation of the synovial membrane of joints. The etiology
and pathogenesis of the disease have not been fully elucidated, and although there are effective symptomatic
treatments, no curative therapy has yet been established.
Follicular regulatory T cells (Tfr cells) play an essential role in suppressing autoimmune diseases such as
rheumatoid arthritis by suppressing the production of IgG autoantibodies that recognize self-antigens and IgE
antibodies involved in allergic responses. However, the underlying differentiation mechanism remains largely
unknown. There is no culture system to induce differentiation of Tfr cells, and clarifying the differentiation
mechanism of Tfr cells is important for (1) clarifying the immunological mechanisms that control autoantibody
production and (2) developing therapeutic agents for autoimmune diseases that target Tfr cells. To elucidate themechanisms of Tfr cell differentiation, chemical biology, which seeks to elucidate complex biological phenomenausing small molecular compounds, could be a useful research strategy. In developing chemical biology, it isimportant to create low-molecular compounds with diversity in structure and bioactivity. Such low-molecularcompounds can be expected to become lead compounds for therapeutic drugs; however even modern
combinatorial synthetic compounds have limited structural diversity. Meanwhile, microbial metabolites, which arerich in diversity of structure and bioactivity, are attracting attention again as a source of bioactive substances.
Actinomycetes, in particular, are known to produce a variety of secondary metabolites in their culture medium,and various bioactive substances have been identified and isolated.
In this study, we aim to search for, identify, and isolate bioactive substances involved in Tfr cell differentiationby evaluating the ability of hundreds of actinomycete culture media to induce Tfr cell differentiation using the Tfr
cell differentiation induction culture system developed by the applicant. Furthermore, by identifying molecules
targeted by bioactive substances and clarifying many molecules involved in Tfr cell differentiation, we aim toelucidate the entire mechanism of Tfr cell differentiation using chemical biology methods. In addition, this study
will particularly focus on the role of Tfr cells in suppressing the onset of autoimmune diseases, and will use arheumatoid arthritis model to evaluate the pharmacological effects of bioactive substances that induce Tfr celldifferentiation. In parallel with the identification of target molecules of bioactive substances, we will introduce alibrary of known active compounds and off-patent drugs and evaluate their ability to induce Tfr cell differentiationin order to develop chemical biology to a high level.
As a result of screening using actinomycete culture extract, we identified an actinomycete strain with potent
Tfr cell differentiation inducing activity. Furthermore, a highly lipophilic fraction of the extract showed Tfr celldifferentiation inducing activity. We are currently trying to identify the bioactive substances in this fraction.
2

Furthermore, screening of a preexisting chemical library led to the discovery of an HDAC inhibitor as a compoundwith Tfr cell differentiation inducing activity. We evaluated each specific inhibitor of HDAC1/2 in autoimmune
rheumatoid arthritis models, and found that each inhibitor markedly inhibited the onset of arthritis. These results
suggest that specific inhibitors of HDAC isozymes are promising candidates for the treatment of rheumatoid
arthritis in the future.

3