2018 Fiscal Year Final Research Report

Mogamulizumab induced immune related adverse events; the impact of Treg depletion

Research Project

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Project/Area Number	16H04713
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Research Field	Tumor therapeutics
Research Institution	Iwate Medical University (2017-2018) Nagoya City University (2016)
Principal Investigator	ISHIDA TAKASHI 岩手医科大学, 医学部, 教授 (80405183)
Co-Investigator(Kenkyū-buntansha)	上田龍三愛知医科大学, 医学部, 教授 (20142169) 伊藤旭名古屋市立大学, 大学院医学研究科, 助教 (00571762) 近藤豊名古屋市立大学, 大学院医学研究科, 教授 (00419897)
Project Period (FY)	2016-04-01 – 2019-03-31
Keywords	CCR4 / 制御性T細胞 / 免疫関連有害事象 / 自己抗体 / 成人T細胞白血病
Outline of Final Research Achievements	The purpose of this study was to determine the mechanisms by which mogamulizumab causes immune-related AEs in patients with ATL. As a result, autoantibodies recognizing human keratinocytes or melanocytes were found in the sera of patients suffering from mogamulizumab-induced erythema multiforme (EM). CDC mediated by autoantibodies against keratinocytes or melanocytes was proportionally related to the severity of the EM. Colocalization of autoantibodies and C1q, suggesting the activation of CDC, was observed in the biopsy specimens of mogamulizumab-induced EM. Consistent with these findings, NGS demonstrated that IgM germline genes had newly emerged and expanded, resulting in IgM repertoire skewing at the time of EM. In conclusion, mogamulizumab elicits autoantibodies playing an important role in skin-related AEs, possibly associated with Treg depletion. This is the first report demonstrating the presence of skin-directed autoantibodies after mogamulizumab treatment.
Free Research Field	血液内科学
Academic Significance and Societal Importance of the Research Achievements	本研究では、モガムリズマブの制御性T細胞(Tregs)除去により、末梢性免疫寛容が破綻し、残存自己反応性B細胞が産生する自己抗体が、免疫関連有害事象の原因となることを明らかにした。現代の科学においても、B細胞の末梢性免疫寛容メカニズム、TregsがB細胞を制御するメカニズムは、明らかとなっていない。本研究成果は、ヒト免疫メカニズムの基盤的理解に貢献するものと考える。さらには、本研究成果は、PD-1、CTLA-4に対する抗体治療で認める免疫関連有害事象のさらなる理解に貢献するものである。