Abstract 5049: Development of huPBMC-NCG mice to study xenogenic graft versus host disease (GVHD)

Abstract

Abstract Graft versus host disease (GVHD) is a severe complication of allogeneic stem cell transplantation for leukemia treatment. NCG mice lacking functional murine T, B, NK cells as well as decreasing functional macrophage and dendritic cells could be used as recipients of human peripheral blood mononuclear cells (huPBMC) for the studies of human GVHD. In this study, huPBMC-NCG mice were developed by the engraftment of huPBMC into unconditioned or irradiated NCG mice. The engraftment kinetics, irradiation effect, and preclinical treatment were explored in these mice. After huPBMC engraftment, NCG mice developed GVHD symptoms, including body weight loss, fur loss, reduced activity, hunched posture and severe ruffling, and eventually led to mortality. We also observed human T cell trafficking to target organs including gut, heart, liver, skin, and lung by flow cytometry and immunohistochemistry. Interestingly, irradiation could significantly accelerate the onset of GVHD following huPBMC engraftment. Meanwhile, irradiated huPBMC-NCG mice presented less variability in the kinetics of GVHD and the frequency of this disease in comparison with unconditioned counterparts, thus providing a more stable model for human GVHD studies. For preclinical studies, we found immunomodulatory drugs including Abatacept (CTLA4-Ig) targeting APC cells or anti-Ly6G antibody targeting neutrophils could alleviate GVHD-associated symptoms along with improving overall survival of huPBMC-NCG mice. Taken together, this study established stable huPBMC-NCG mice to mimic the onset and development of human GVHD, which was helpful for the development of therapeutic intervention. Citation Format: Cunxiang Ju, Hongyan Sun, Dingyu Wang, Shiying Guo, Mingkun Zhang, Hainan Wu, Shuai Li, Chao Ju, Jing Zhao, Xiang Gao. Development of huPBMC-NCG mice to study xenogenic graft versus host disease (GVHD) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5049.