Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model.

Rintaro Ono
Takashi Watanabe
Eiryo Kawakami
Makoto Iwasaki
Mariko Tomizawa-Murasawa
Masashi Matsuda
Yuho Najima
Shinsuke Takagi
Saera Fujiki
Rumi Sato
Yoshiki Mochizuki
Hisahiro Yoshida
Kaoru Sato
Hiromasa Yabe
Shunichi Kato
Yoriko Saito
Shuichi Taniguchi
Leonard D. Shultz, The Jackson Laboratory
Osamu Ohara
Masayuki Amagai
Haruhiko Koseki
Fumihiko Ishikawa

Abstract

BACKGROUND: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence.

METHODS: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34

FINDINGS: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation.

INTERPRETATION: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD.