Professor Kouji Matsushima is awarded the 2019 ICIS Honorary Lifetime Membership Award in recognition of his exceptional contributions to cytokine and chemokine research, from basic research to translational research and to clinical therapies and committment to ICIS as senior council member of the ICS (International Cytokine Society) and as president of the Cytokines 2017 in Kanazawa.

Kouji Matsushima, MD, PhD
Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan

Prof. Kouji Matsushima is currently Professor of Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science. Dr. Matsushima is awarded the 2019 ICIS Honorary Lifetime Membership Award in recognition of his exceptional contributions to cytokine and chemokine research, from basic research to translational research and to clinical therapies. In addition to his major scientific achievement in cytokine and chemokine fields, he served as a senior council member of the ICS (International Cytokine Society) and as president of the Cytokines 2017, 5th Annual Meeting of the International Cytokine & Interferon Society organizing committee.

Dr. Matsushima graduated from Kanazawa University Medical School in 1978 and received his Ph. D. from Kanazawa University, Graduate School of Medicine in 1982. After getting his degree, he immediately joined the National Cancer Institute, USA as a Fellow in the Biological Response Modifiers Program located in Frederick, MD.

The prelude to the discovery of chemokines: There was fierce competition in cDNA cloning research in the 1980s. Dr. Matsushima joined the laboratory of Dr. Joost J. Oppenheim in October 1982. He succeeded in purifying human IL-1alpha and IL 1beta. His purification confirmed the correctness of cDNA cloning of human IL 1 beta precursor by Phil Auron et al. in 1984, and identified the mature and active form of human IL 1beta (cleavage site of ICE/Caspase 1). He also confirmed the biological activities ascribed previously to IL-1, such as thymocyte co-mitogenic activity, stimulation of fibroblast proliferation, endogenous pyrogen activity and acute phase protein-inducing activity.  

Purification and cDNA cloning of human interleukin-8 (CXCL8): In the 1970’s, leukocyte-derived neutrophil chemotactic factor (NCF) and monocyte chemotactic factor (MCF) were described in the literature, but their molecular nature remained unclear. Before his purification and cDNA cloning of IL-8, IL-1 and tumor necrosis factor had been considered responsible for the chemotactic activity. To his surprise, neither his purified IL-1s nor recombinant TNF alpha displayed the chemotactic activity. The neutrophil chemotactic activity was detected in the conditioned media that he used for the IL-1 purification. In 1986, Dr. Teizo Yoshimura joined Ed Leonard’s laboratory as a postdoctoral fellow and Dr. Matsushima mentioned to Dr. Yoshimura the mysterious and intriguing phenomenon of neutrophil chemotactic activity in the conditioned media of activated human leukocytes, and they decided to characterize and clone the cDNA in collaboration (KM acted as PI). They could easily separate neutrophil chemotactic activity from IL-1 activity by HPLC gel filtration, and succeeded in purifying 400 μg of NCF from 4 L of LPS- stimulated human PBMC conditioned medium. Dr. Matsushima cloned, by himself, from the construction of the cDNA library to DNA sequence analysis, the cDNA from LPS-stimulated human PBMCs based on the amino acid sequence information of the purified NCF, To confirm that the cloned cDNA really did encode the NCF protein, they chemically synthesized 72 amino acids deduced from the cDNA sequence, expressed the recombinant NCF in E. coli. made a monoclonal antibody against the recombinant NCF. Dr. Matsushima published a paper describing the cDNA cloning of NCF in J. Exp. Med. In 1988. Dr. Howard Young can add a personal note to this story as he was in my office a bit late in the day and Dr. Matsushima came rushing in with his x-ray film showing what appeared to be a positive plaque and indeed the one spot turned out to be IL-8.

Purification and cDNA sequencing of MCAF/MCP-1(CCL2) : When Dr. Chris Larsen from Denmark joined NCI in 1988, he re-examined the MCF activity in the conditioned media that he used for IL-1 purification, and found that there was too much activity in the media, and that it was necessary to make a 1,000 fold dilution in order to detect MCF activity (it was well known that too high a concentration of chemotactic factor inhibits cell migration). Since MCF activity could be adsorbed by a heparin column in the same way as IL-8, it was really easy to purify MCF from THP-1 conditioned media, and Dr. Matsushima completed the entire purification procedure in a week (J. Exp. med. 1989). However, it took several weeks to obtain partial amino acid sequence information for MCF because of a blockade of the N-terminal by pyroglutamate formation. Dr. Matsushima collaborated with Dr. Masaaki Yamada (Dainippon Pharmaceuticals. Co. Ltd.) in the cDNA cloning of MCF. They successfully obtained international patent rights. Independently, Dr. Yoshimura, in Dr. Leonard’s lab, purified the same MCF protein simultaneously, but independently from different cell line conditioned media. Dr. Matsushima named this molecule MCAF based on its chemotactic and activation effects on monocytes, while Dr. Yoshimura named it MCP-1.  

Dr. Matsushima was awarded tenure at the NCI but in 1990 he returned to Kanazawa University, his alma mater and became a professor at the age of 37. In his new position, he began trying to establish the role of chemokines in inflammatory and immune diseases. A number of papers resulted from these efforts, including Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8 (Nature 1993), Prevention of proteinuria by the administration of anti-interleukin 8 antibody in experimental acute immune complex-induced glomerulonephritis (J Exp Med. 1994.), and Intervention of crescentic glomerulonephritis by antibodies to monocyte chemotactic and activating factor (Faseb J. 1996.) Those studies first established the in vivo roles of chemokines controlling cell-type specific leukocyte infiltration during inflammation. He moved to The University of Tokyo in 1996, and made numerous monoclonal antibodies against N-terminal regions of human chemokine receptors using hybridoma technology, and he found that only one clone among several hundred clones recognizing CHO-chemokine receptor transfectants recognized natural CCR4 on human T lymphocytes. He subsequently found that CCR4 is selectively expressed on the CD4+Th2 population and also aberrantly and highly expressed on adult T cell leukemia (ATL) cells (in collaboration with Dr. Osamu Yoshie). He then collaborated with Kyowa-Hakko Co. Ltd., Japan to convert the murine monoclonal antibody to a humanized antibody with potent ADCC activity and succeeded in the clinical development of this novel reagent. This humanized anti-CCR4 antibody (mogamulizumab) has been approved as a therapy for adult T cell leukemia (ATL), and other types of CCR4+T cell leukemia and lymphoma, such as Sezary’s syndrome and Mycosis fungoides in the USA, Europe and Japan. In addition, this antibody also turned out to deplete Treg cells (CCR4++) very efficiently. Therefore, numerous clinical trials of this anti-CCR4 antibody particularly in combination with various immune-check point antibodies are being carried out as a means to deplete regulatory T cells in cancer patients.

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