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 (+10 others)
2019 EBioMedicine  
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 + CD38 − CD45RA − haematopoietic stem/progenitor cells (HSPCs) into hIL-6 transgenic NOD/ SCID/Il2rgKO (NSG)
more » ... wborns, and compared GVHD progression with NSG newborns receiving CB CD34 − cells mimicking acute GVHD. We characterised human immune cell subsets, target organ infiltration, T-cell repertoire (TCR) and transcriptome in the humanised mice. 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. GVHD is an important complication of haematopoietic stem cell transplantation. Mouse models and clinical experience suggested important roles of activated T cells both in acute and chronic GVHD. GWAS studies implicated IL-6 in pathogenesis of chronic GVHD and anti-IL6R Ab has been reported to ameliorate disease status in patients with chronic GVHD. Added value of this study We created a chronic GVHD humanised mouse model by transplanting human HSPCs into hIL-6 TG NSG newborns. In this model, activation of both human T cells and macrophages was associated with tissue damage in skin, lung, and liver. We also created acute
doi:10.1016/j.ebiom.2019.02.001 fatcat:2ucbqmve4bayrdcuypanxpkylu