| 1. |
Kenichiro Hirotani, Kazufumi Kunimura, Takeshi Iwasaki, Yoshinori Fukui, Kiyoko Kato, A case of high-grade VUE diagnosed by additional immunostaining rather than H&E staining alone, Placenta, 10.1016/j.placenta.2023.08.053, 141, 94-94, 2023.09. |
| 2. |
Kentaro Hata, Toyoshi Yanagihara, Keisuke Matsubara, Kazufumi Kunimura, Daisuke Eto, Kunihiro Suzuki, Kazuya Tsubouchi, Satoshi Ikegame, Yoshinori Fukui, Isamu Okamoto, Altered macrophage phenotypes in a case of autoimmune pulmonary alveolar proteinosis, ERJ Open Research, 10.1183/23120541.00500-2023, 00500-2023, 2023.09. |
| 3. |
Toyoshi Yanagihara, Kentaro Hata, Keisuke Matsubara, Kazufumi Kunimura, Kunihiro Suzuki, Kazuya Tsubouchi, Satoshi Ikegame, Yoshihiro Baba, Yoshinori Fukui, Isamu Okamoto, Mass cytometry analysis of B-cell populations in extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue of the lung, Annals of Hematology, 10.1007/s00277-023-05391-3, 2023.07. |
| 4. |
Toyoshi Yanagihara, Kentaro Hata, Keisuke Matsubara, Kazufumi Kunimura, Kunihiro Suzuki, Kazuya Tsubouchi, Satoshi Ikegame, Yoshihiro Baba, Yoshinori Fukui, Isamu Okamoto, Exploratory mass cytometry analysis reveals immunophenotypes of cancer treatment-related pneumonitis, eLife, 10.7554/elife.87288.1, 12, RP87288, 2023.06, Anti-cancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.. |
| 5. |
Kenji Morino*, Kazufumi Kunimura*, Yuki Sugiura, Yoshihiro Izumi, Keisuke Matsubara, Sayaka Akiyoshi, Rei Maeda, Kenichiro Hirotani, Daiji Sakata, Seiya Mizuno, Satoru Takahashi, Takeshi Bamba, Takehito Uruno, Yoshinori Fukui, Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury, Frontiers in Immunology, 10.3389/fimmu.2023.1131146, 2023.03. |
| 6. |
Toyoshi Yanagihara, Kentaro Hata, Kunihiro Suzuki, Keisuke Matsubara, Kazufumi Kunimura, Kazuya Tsubouchi, Daisuke Eto, Hiroyuki Ando, Maki Uehara, Satoshi Ikegame, Yoshinori Fukui, Isamu Okamoto, Expansion of ST2-expressing macrophages in a patient with bronchiolitis obliterans syndrome, ERJ Open Research, 10.1183/23120541.00033-2023, 2023.03. |
| 7. |
Kentaro Hata, Toyoshi Yanagihara, Keisuke Matsubara, Kazufumi Kunimura, Kunihiro Suzuki, Kazuya Tsubouchi, Daisuke Eto, Hiroyuki Ando, Maki Uehara, Satoshi Ikegame, Yoshihiro Baba, Yoshinori Fukui, Isamu Okamoto, Mass cytometry identifies characteristic immune cell subsets in bronchoalveolar lavage fluid from interstitial lung diseases, Frontiers in Immunology, 10.3389/fimmu.2023.1145814, 14, 1145814, 2023.03. |
| 8. |
Kazufumi Kunimura, Sayaka Akiyoshi, Takehito Uruno, Keisuke Matsubara, Daiji Sakata, Kenji Morino, Kenichiro Hirotani, Yoshinori Fukui, DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis, The Journal of Allergy and Clinical Immunology, 10.1016/j.jaci.2023.01.029, 2023.02. |
| 9. |
Kazufumi Kunimura, Kazuhiko Yamamura, Takeshi Nakahara, Makiko Kido-Nakahara, Takehito Uruno, Yoshinori Fukui, Identification of a functional DOCK8 gene polymorphism associated with atopic dermatitis, Allergy, 10.1111/all.15429, 2022.07. |
| 10. |
Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Kounosuke Oisaki, Daisuke Takaya, Daiji Sakata, Yoshihiro Izumi, Takaya Togo, Yuko Hattori, Kazufumi Kunimura, Testuya Sakurai, Teruki Honma, Takeshi Bamba, Masafumi Nakamura, Motomu Kanai, Makoto Suematsu, Yoshinori Fukui, Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2022.04.035, 609, 183-188, 2022.04. |
| 11. |
Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Daiji Sakata, Yoshihiro Izumi, Tetsuya Sakurai, Yuko Hattori, Eiji Oki, Naoto Kubota, Koshiro Nishimoto, Masafumi Oyama, Kazufumi Kunimura, Takuto Ohki, Takeshi Bamba, Hideaki Tahara, Michiie Sakamoto, Masafumi Nakamura, Makoto Suematsu, Yoshinori Fukui, Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells, International Immunology, 10.1093/intimm/dxac002, 2022.01, Abstract
Effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T-cell transfer and immune checkpoint blockade. Although SULT2B1b is known to sulfate oxysterols and inactivate their tumor-promoting activity, the expression levels of cholesterol hydroxylases, which mediate oxysterol production, are low in SULT2B1b-expressing cancers. Therefore, SULT2B1b inhibition could be a therapeutic strategy to disrupt tumor immune evasion in oxysterol-non-producing cancers. Thus, our findings define a previously unknown mechanism for tumor immune evasion and provide a novel insight into the development of effective immunotherapies.. |
| 12. |
Kazufumi Kunimura, Yoshinori Fukui, The molecular basis for IL-31 production and IL-31-mediated itch transmission: from biology to drug development, International Immunology, 10.1093/intimm/dxab065, 2021.09, Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory skin diseases in the world. It is characterized by recurrent eczematous lesions and intense itch, and many cytokines are involved in the pathogenesis of AD. Among them, much attention has been paid to interleukin 31 (IL-31) as an AD-associated itch mediator. IL-31 is mainly produced by CD4+ helper T cells and transmits the signals via a heterodimeric receptor composed of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR), both of which are expressed in dorsal root ganglion (DRG) neurons. However, the molecular mechanisms of how IL-31 is produced in helper T cells upon stimulation and transmits the itch sensation to the brain were largely unknown. Recently, by using original mouse models of AD, we have identified endothelial PAS domain 1 (EPAS1) and neurokinin B (NKB) as key molecules critical for IL-31 production and IL-31-mediated itch transmission, respectively. These molecules could be novel drug targets for AD-associated itch. This review highlights our recent findings, which show the functional significance of these molecules in the IL-31-induced itch sensation, referring to their application to drug development.. |
| 13. |
Keisuke Matsubara*, Kazufumi Kunimura*, Nana Yamane, Ryosuke Aihara, Tetsuya Sakurai, Daiji Sakata, Takehito Uruno, Yoshinori Fukui, DOCK8 deficiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2021.04.094, 559, 135-140, 2021.06. |
| 14. |
Yasuhisa Kamikaseda, Takehito Uruno, Kazufumi Kunimura, Akihito Harada, Kuniko Saiki, Kounosuke Oisaki, Daiji Sakata, Takeshi Nakahara, Makiko Kido-Nakahara, Motomu Kanai, Seiji Nakamura, Yasuyuki Ohkawa, Masutaka Furue, Yoshinori Fukui, Targeted inhibition of EPAS1–driven IL-31 production by a small-molecule compound, Journal of Allergy and Clinical Immunology, 10.1016/j.jaci.2021.03.029, 148, 2, 633-638, 2021.04, Background
IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibition of IL-31 production remain unexploited. IL-31 production by Th cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1.
Objective
We aimed at developing small-molecule inhibitors that selectively block IL-31 production by Th cells.
Methods
We generated the reporter cell line that inducibly expressed EPAS1 in the presence of doxycycline to mediate Il31 promoter activation, and we screened 9600 chemical compounds. The selected compounds were further examined by using Th cells from a spontaneous mouse model of AD and Th cells from patients with AD.
Results
We have identified 4-(2-(4-isopropylbenzylidene)hydrazineyl)benzoic acid (IPHBA) as an inhibitor of IL31 induction. Although IPHBA did not affect nonspecific T-cell proliferation, IPHBA inhibited antigen-induced IL-31 production by Th cells from both an AD mouse model and patients with AD without affecting other cytokine production and hypoxic responses. In line with this, itch responses induced by adoptive transfer of IL-31–producing Th cells were attenuated when mice were orally treated with IPHBA. Mechanistically, IPHBA inhibited the association between EPAS1 and SP1, resulting in defective recruitment of both transcription factors to the specific sites of the IL31 promoter. We also determined the structure-activity relationship of IPHBA by synthesizing and analyzing 201 analogous compounds.
Conclusion
IPHBA could be a potential drug leading to inhibition of EPAS1-driven IL-31 production.. |
| 15. |
Ryosuke Aihara*, Kazufumi Kunimura*, Mayuki Watanabe, Takehito Uruno, Nana Yamane, Tetsuya Sakurai, Daiji Sakata, Fusanori Nishimura, Yoshinori Fukui, DOCK8 controls survival of group 3 innate lymphoid cells in the gut through Cdc42 activation., International Immunology, 10.1093/intimm/dxaa066, 33, 3, 149-160, 2020.09.  |
| 16. |
Kazufumi Kunimura, Daiji Sakata, Xin Tun, Takehito Uruno, Miho Ushijima, Tomoya Katakai, Akira Shiraishi, Ryosuke Aihara, Yasuhisa Kamikaseda, Keisuke Matsubara, Hirokazu Kanegane, Shinichiro Sawa, Gérard Eberl, Shouichi Ohga, Yasunobu Yoshikai, Yoshinori Fukui, S100A4 Protein Is Essential for the Development of Mature Microfold Cells in Peyer's Patches., Cell reports, 10.1016/j.celrep.2019.10.091, 29, 9, 2823-2834, 2019.11. |
| 17. |
Daiji Sakata, Takehito Uruno, Keisuke Matsubara, Tsugunobu Andoh, Kazuhiko Yamamura, Yuki Magoshi, Kazufumi Kunimura, Yasuhisa Kamikaseda, Masutaka Furue, Yoshinori Fukui, Selective role of neurokinin B in IL-31-induced itch response in mice., The Journal of allergy and clinical immunology, 10.1016/j.jaci.2019.06.031, 144, 4, 1130-1133, 2019.10. |
| 18. |
Miho Ushijima, Takehito Uruno, Akihiko Nishikimi, Fumiyuki Sanematsu, Yasuhisa Kamikaseda, Kazufumi Kunimura, Daiji Sakata, Takaharu Okada, Yoshinori Fukui, The Rac Activator DOCK2 Mediates Plasma Cell Differentiation and IgG Antibody Production., Frontiers in immunology, 10.3389/fimmu.2018.00243, 9, 243-243, 2018.02, A hallmark of humoral immune responses is the production of antibodies. This process involves a complex cascade of molecular and cellular interactions, including recognition of specific antigen by the B cell receptor (BCR), which triggers activation of B cells and differentiation into plasma cells (PCs). Although activation of the small GTPase Rac has been implicated in BCR-mediated antigen recognition, its precise role in humoral immunity and the upstream regulator remain elusive. DOCK2 is a Rac-specific guanine nucleotide exchange factor predominantly expressed in hematopoietic cells. We found that BCR-mediated Rac activation was almost completely lost in DOCK2-deficient B cells, resulting in defects in B cell spreading over the target cell-membrane and sustained growth of BCR microclusters at the interface. When wild-type B cells were stimulated in vitro with anti-IgM F(ab')2 antibody in the presence of IL-4 and IL-5, they differentiated efficiently into PCs. However, BCR-mediated PC differentiation was severely impaired in the case of DOCK2-deficient B cells. Similar results were obtained in vivo when DOCK2-deficient B cells expressing a defined BCR specificity were adoptively transferred into mice and challenged with the cognate antigen. In addition, by generating the conditional knockout mice, we found that DOCK2 expression in B-cell lineage is required to mount antigen-specific IgG antibody. These results highlight important role of the DOCK2-Rac axis in PC differentiation and IgG antibody responses.. |
