Novel Autologous Regulatory T-Cell Therapy Ameliorates DSS-Induced Colitis in Humanized Mice.

Abstract

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex immune-mediated pathogenesis. The efficacy of human-specific cellular immunotherapies and biological medications cannot be accurately evaluated using traditional murine IBD models. Therefore, a humanized mouse model of IBD is necessary. Regulatory T cells (Tregs) are critical for maintaining intestinal immune homeostasis and may have therapeutic potential for treating IBD.

Methods: Donor peripheral blood mononuclear cells (PBMCs) were used to reconstitute the human immune system in NOG mice and for Treg isolation. T cells were sorted and stimulated with anti-CD3 and anti-CD28 in the presence of irradiated feeder cells to prepare Treg cells. Two weeks after PBMC reconstitution in NOG mice, colitis was induced with dextran sodium sulfate (DSS). The expanded Treg cells were administered intravenously. Ozanimod was used as a positive control.

Results: After expansion, 65.4% of the live CD4+ cells were Foxp3+CD25+ Treg cells and 14.5% were non-Treg cells. The mean human leukocyte (hCD45+) engraftment rate in the humanized mice was 56.5% ± 4.5%. Autologous Treg-cell therapy significantly reduced the disease activity index by 78% on day 7. Colonic length was preserved, and colonic inflammation was reduced in mice treated with Treg cells. Immunohistology revealed reduced human T-cell infiltration in Treg-treated mice.

Conclusions: Autologous Treg therapy ameliorated the symptoms of DSS-induced colitis in a humanized mouse model. The autologous PBMC-humanized DSS-induced colitis model may serve as a robust preclinical platform for evaluating the efficacy of personalized Treg cell therapy for IBD.