NSG Mice Engrafted with Human PBMC Provide a Robust Platform for Preclinical Testing of Immunomodulatory Therapeutics Relevant to GvHD, Autoimmunity, and Oncology

Abstract

NSG mice engraft human PBMC and allow efficacy testing of immunomodulatory drugs in a GvHD setting. Engraftment is progressive and at d5 PBL has 10% human cells with a CD4:CD8 T cell ratio of 3:1. The CD4 cells are 30% CD45RO− CCR7+ naïve (Tn), 40% CD45RO+ CCR7+ central memory (Tcm) and 10% CD45RO+ CCR7− effector memory (Tem). The CD8 cells at d5 contain 9% Tn, 3% Tcm, and 5% Tem. At d18 human cells are 70% with a CD4:CD8 ratio of 1:3, 0% Tn, 10% Tcm and are 22% CD4 Tem and 52% CD8 Tem. Engrafted mice were treated either prophylactically (day −1) or therapeutically (day 5) with Abatacept or an unknown test article. PBL at d10 post engraftment from mice treated at day −1 showed human cells at 14.6%, 2.2%, and 1.6% for vehicle, Abatacept, and test article, respectively. The Abatacept group were primarily CD4 Tn. Abatacept and test article treated mice showed 100% survival, almost no tissue infiltration, normal body weight, and were healthier based on disease activity index (DAI) scores. When dosed therapeutically, human cells at d18 were 67.3%, 16.9%, and 37.9%, respectively. Both treatments suppressed T cell expansion, maintained a 3:1 CD4:CD8 ratio and decreased development of the CD8 Tem pool (CD8 Tem 32.7%, 15.4%, and 4.9%, respectively). 100% of the d5 dosed Abatacept group survived, maintained body weight, and had improved DAI. 70% of the d5 dosed test article group survived and at d20 began losing body weight and accumulated poor DAI scores. The data presented here provide a detailed analysis of activated human T cell pools and progression of GvHD in NSG recipients of human PBMC. The model allows detailed analysis of in vivo modulation of T cell activity and therefore enables rapid evaluation of therapies relevant to not only GvHD, but to autoimmunity and oncology.