Induction of persistent lung transplant tolerance by IL-2 complex-stimulated regulatory T cells: a study for the clinical application

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08778
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Kyoto University
• Principal Investigator: Yamada Yoshito 京都大学, 医学研究科, 特定病院助教 (80375691)
• Co-Investigator(Kenkyū-buntansha): 吉野 一郎 千葉大学, 大学院医学研究院, 教授 (40281547) ; 本橋 新一郎 千葉大学, 大学院医学研究院, 教授 (60345022) ; 鈴木 秀海 千葉大学, 医学部附属病院, 講師 (60422226)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 肺移植術後拒絶反応 / IL-2複合体 / 制御性T細胞 / 三次リンパ構造 / 慢性期肺移植片機能不全

Outline of Final Research Achievements

Using targeted interleukin-2 (IL-2) pre-treatment in fully immunocompetent mice, we here achieved acceptance of　fully mismatched lung allografts that remained functional for >90 days. These tolerogenic effects were controlled by graft-homing forkhead box p3 (Foxp3)+ regulatory T (Treg) cells. Thus, although circulating Treg cell counts rapidly returned to baseline following IL-2 pre-treatment, Foxp3+ Treg cells persisted in peribronchial areas of the grafted lung, forming bronchus-associated lymphoid tissues (BALT). Foxp3-transgenic mice with inducible deletion of Foxp3+ cells were unable to form organized BALT containing Foxp3+ Treg cells, as evidenced using microscopy-based calculation of ordered distribution, and these mice acutely rejected their lung allografts. Collectively, we report a high-intensity and biased IL-2 pre-conditioning able to induce Foxp3-controlled BALT to facilitate acceptance of vascularized and ventilated lung allografts without the need of immunosuppression.

Free Research Field

移植免疫

Academic Significance and Societal Importance of the Research Achievements

肺移植は末期呼吸器疾患に対する治療手段の一つである。1998年の本邦初症例以来、症例数は増加しており、一般呼吸器外科診療の一つとなった。一方で、肺移植術後慢性期の術後成績は長年停滞傾向となっている。本研究ではIL-2複合体によりマウス肺移植実験で長期に渡ってグラフト保護効果を示した。本法を用いた免疫制御法で、臨床肺移植で課題となっている慢性期免疫抑制治療戦略を改善できると考える。